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    Clinical Trial Results:
    A Phase III, Randomized, Multicenter, Double-Blind, Placebo-Controlled Clinical Trial of Omalizumab in Patients with Chronic Rhinosinusitis With Nasal Polyps

    Summary
    EudraCT number
    		 2017-001724-22
    Trial protocol
    		 GB   DE   CZ   PT   PL  
    Global end of trial date
    11 Mar 2019

    Results information
    Results version number
    		 v2(current)
    This version publication date
    05 Apr 2020
    First version publication date
    01 Mar 2020
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    GA39688
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03280550
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche, Ltd.
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, 4070
    Public contact
    F. Hoffmann-La Roche, Ltd., F. Hoffmann-La Roche, Ltd., +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche, Ltd., F. Hoffmann-La Roche, Ltd., +41 616878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    11 Mar 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Mar 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Mar 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the efficacy and safety of omalizumab compared with placebo in adult patients with chronic rhinosinusitis with nasal polyps who have had an inadequate response to standard-of-care treatments.
    Protection of trial subjects
    This study was conducted in full conformance with the ICH E6 guideline for Good Clinical Practice and the principles of the Declaration of Helsinki, or the laws and regulations of the country in which the research was conducted, whichever afforded the greater protection to the individual. All study subjects were required to read and sign and informed consent form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Nov 2017
    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
    Canada: 7
    Country: Number of subjects enrolled
    Mexico: 2
    Country: Number of subjects enrolled
    United States: 33
    Country: Number of subjects enrolled
    Czech Republic: 4
    Country: Number of subjects enrolled
    Poland: 22
    Country: Number of subjects enrolled
    Russian Federation: 3
    Country: Number of subjects enrolled
    Ukraine: 42
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Portugal: 21
    Country: Number of subjects enrolled
    United Kingdom: 1
    Worldwide total number of subjects
    138
    EEA total number of subjects
    51
    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)
    113
    From 65 to 84 years
    25
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 At the first visit of the 5-week screening/run-in period, participants were asked to standardize their nasal corticosteroids to a regimen of mometasone, 200 micrograms twice a day (BID). If intolerant to a BID regimen, then they remained on a stable dosage of mometasone once a day (QD) during the run-in period and throughout the treatment period.

    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, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants received matching placebo as a subcutaneous injection once every 2 weeks or once every 4 weeks. The dose and dosing frequency was determined by serum total IgE level and body weight using the study-drug dosing table. All participants were also treated during the entire study with intranasal corticosteroids (mometasone nasal spray) as background therapy.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo was administered subcutaneously every 2 or 4 weeks by qualified personnel who were not involved with conducting safety or efficacy evaluations using a disposable 25-gauge needle in the deltoid region of the right or left arm. Alternatively, the injections could have been administered in the thigh, if medically significant reasons precluded administration in the deltoid region. Because the solution is slightly viscous, the injection may have taken 5-10 seconds to administer. The dose (mg) and dosing frequency were determined by serum total IgE level (IU/mL) (measured before the start of treatment via central laboratory) and body weight (kg). Assignment of the study drug dose was determined by using the study drug-dosing table. The placebo equivalent of doses of greater than (>) 150 mg were divided among more than one injection site to limit injections to no more than 150 mg per site.

    Arm title
    		 Omalizumab
    Arm description
    		 Participants received omalizumab as a subcutaneous injection once every 2 weeks (q2w) or once every 4 weeks (q4w). The dose (from 75 mg up to 600 mg) and dosing frequency (q2w or q4w) was determined by serum total IgE level and body weight using the study-drug dosing table. All participants were also treated during the entire study with intranasal corticosteroids (mometasone nasal spray) as background therapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Omalizumab
    Investigational medicinal product code
    Other name
    Xolair IGE025 RO5489789
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Omalizumab was administered subcutaneously every 2 or 4 weeks by qualified personnel who were not involved with conducting safety or efficacy evaluations using a disposable 25-gauge needle in the deltoid region of the right or left arm. Alternatively, the injections could have been administered in the thigh, if medically significant reasons precluded administration in the deltoid region. Because the solution is slightly viscous, the injection may have taken 5-10 seconds to administer. The dose (mg) and dosing frequency were determined by serum total IgE level (IU/mL) (measured before the start of treatment via central laboratory) and body weight (kg). Assignment of the study drug dose was determined by using the study drug-dosing table. Doses of greater than (>) 150 mg were divided among more than one injection site to limit injections to no more than 150 mg per site.

    Number of subjects in period 1
    		Placebo Omalizumab
    Started
    66
    72
    Completed
    64
    69
    Not completed
    2
    3
         Consent withdrawn by subject
    2
    2
         Physician decision
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received matching placebo as a subcutaneous injection once every 2 weeks or once every 4 weeks. The dose and dosing frequency was determined by serum total IgE level and body weight using the study-drug dosing table. All participants were also treated during the entire study with intranasal corticosteroids (mometasone nasal spray) as background therapy.

    Reporting group title
    Omalizumab
    Reporting group description
    		 Participants received omalizumab as a subcutaneous injection once every 2 weeks (q2w) or once every 4 weeks (q4w). The dose (from 75 mg up to 600 mg) and dosing frequency (q2w or q4w) was determined by serum total IgE level and body weight using the study-drug dosing table. All participants were also treated during the entire study with intranasal corticosteroids (mometasone nasal spray) as background therapy.

    Reporting group values
    		 Placebo Omalizumab Total
    Number of subjects
    		 66 72 138
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 54 59 113
        From 65-84 years
    		 12 13 25
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 52.2 ± 11.6 50.0 ± 14.5 -
    Sex: Female, Male
    Units: participants
        Female
    		 25 25 50
        Male
    		 41 47 88
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 2 2
        Asian
    		 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 2 2
        White
    		 66 65 131
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 0 3 3
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 5 9 14
        Not Hispanic or Latino
    		 61 62 123
        Unknown or Not Reported
    		 0 1 1
    Geographic Region of Enrollment
    Units: Subjects
        North America
    		 19 23 42
        ex-North America
    		 47 49 96
    Participants with Asthma Comorbidity and Aspirin Sensitivity
    Asthma comorbidity was defined as asthma history at screening and having used medication for asthma or received a prescription for any asthma medication in the last 12 months prior to screening.
    Units: Subjects
        Asthmatic and Aspirin Sensitive
    		 10 14 24
        Asthmatic and Not Aspirin Sensitive
    		 22 28 50
        Not Asthmatic
    		 34 30 64
    Mometasone Prescribed Daily Dose at Baseline
    Units: Subjects
        200 micrograms
    		 4 4 8
        400 micrograms
    		 62 68 130
    Nasal Polyp Score (NPS) at Baseline
    Total NPS ranges from 0 to 8 (sum of 0-4 for left and right nasal passage scores per the following criteria), with a lower score indicating smaller-sized nasal polyps: 0 = No polyps; 1 = Small polyps in middle meatus not reaching below inferior border of the middle turbinate; 2 = Polyps reaching below lower border of the middle turbinate; 3 = Large polyps reaching lower border of the inferior turbinate or polyps medial to the middle turbinate; and 4 = Large polyps causing complete obstruction of the inferior nasal cavity. Baseline was the last assessment on or before the date of randomization.
    Units: Score on a scale
        arithmetic mean (standard deviation)
    		 6.3 ± 0.9 6.2 ± 1.0 -
    Average Daily Nasal Congestion Score at Baseline
    The Nasal Congestion Score (NCS) was assessed daily by the participant via an electronic diary as the response to the following question: Is your nose blocked? The four available response options were scored from 0 (no symptoms) to 3 (severe symptoms): 0 = Not at all; 1 = Mild; 2 = Moderate; and 3 = Severe. Baseline was defined as the average of the daily values recorded during the 7-day interval ending on the latest day prior to randomization such that the prior 7-day interval includes a recorded value on at least 4 of the 7 days of that interval.
    Units: Score on a scale
        arithmetic mean (standard deviation)
    		 2.5 ± 0.6 2.4 ± 0.7 -
    Average Daily Sense of Smell Score at Baseline
    The Sense of Smell Score was assessed daily by the participant via an electronic diary as the response to the following question: Is your sense of smell reduced? The four available response options were scored from 0 (no symptoms) to 3 (severe symptoms): 0 = Not at all; 1 = Mild; 2 = Moderate; and 3 = Severe. Baseline was defined as the average of the daily values recorded during the 7-day interval ending on the latest day prior to randomization such that the prior 7-day interval includes a recorded value on at least 4 of the 7 days of that interval.
    Units: Score on a scale
        arithmetic mean (standard deviation)
    		 2.8 ± 0.4 2.6 ± 0.8 -
    Average Daily Posterior Rhinorrhea Score at Baseline
    The Posterior Rhinorrhea Score was assessed daily by the participant via an electronic diary as the response to the following question: Do you feel dripping at the back of the nose? The four available response options were scored from 0 (no symptoms) to 3 (severe symptoms): 0=Not at all; 1=Mild; 2=Moderate; and 3=Severe. Baseline was defined as the average of the daily values recorded during the 7-day interval ending on the latest day prior to randomization such that the prior 7-day interval includes a recorded value on at least 4 of the 7 days of that interval.
    Units: Score on a scale
        arithmetic mean (standard deviation)
    		 2.0 ± 0.9 1.7 ± 0.9 -
    Average Daily Anterior Rhinorrhea Score at Baseline
    The Anterior Rhinorrhea Score was assessed daily by the participant via an electronic diary as the response to the following question: Do you have a runny nose? The four available response options were scored from 0 (no symptoms) to 3 (severe symptoms): 0=Not at all; 1=Mild; 2=Moderate; and 3=Severe. Baseline was defined as the average of the daily values recorded during the 7-day interval ending on the latest day prior to randomization such that the prior 7-day interval includes a recorded value on at least 4 of the 7 days of that interval.
    Units: Score on a scale
        arithmetic mean (standard deviation)
    		 2.1 ± 0.8 1.9 ± 0.8 -
    Daily Total Nasal Symptom Score (TNSS) at Baseline
    The Total Nasal Symptom Score (TNSS) was defined as the sum of the four individual scores for Nasal Congestion Score, Anterior Rhinorrhea Score, Posterior Rhinorrhea Score, and Sense of Smell Score, ranging from 0 (no symptoms) to 12 (most severe symptoms), assessed daily by the participant via an electronic diary. Baseline was defined as the average of the daily values recorded during the 7-day interval ending on the latest day prior to randomization such that the prior 7-day interval includes a recorded value on at least 4 of the 7 days of that interval.
    Units: Score on a scale
        arithmetic mean (standard deviation)
    		 9.3 ± 1.9 8.6 ± 2.5 -
    Total Sino-Nasal Outcome Test-22 (SNOT-22) Score at Baseline
    The SNOT-22 Questionnaire, a disease specific HRQoL measure, comprises a list of 22 symptoms and social or emotional consequences of the nasal disorder. Every participant was asked to rate how severe each problem had been for them over the past 2 weeks on a scale from 0 (no problem at all) to 5 (problem as bad as it can be). The total score is the sum of the scores for all 22 items, ranging from 0 to 110, with a lower score indicating less disease and better HRQoL. Baseline was defined as the last assessment on or before the date of randomization.
    Units: Score on a scale
        arithmetic mean (standard deviation)
    		 60.5 ± 15.3 59.8 ± 19.7 -
    University of Pennsylvania Smell Identification Test (UPSIT) Score at Baseline
    The UPSIT is a 40-question instrument that measures an individual’s ability to detect odors and ranges from 0 to 40, with a higher score indicating a better sense of smell. It is a self-administered "scratch-and-sniff" test provided in booklets that have 40 microencapsulated odorants, each with a multiple-choice option for the response. The number of correct responses is summed to provide a total score. Baseline was defined as the last assessment on or before the date of randomization.
    Units: Score on a scale
        arithmetic mean (standard deviation)
    		 13.9 ± 7.4 12.8 ± 7.9 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received matching placebo as a subcutaneous injection once every 2 weeks or once every 4 weeks. The dose and dosing frequency was determined by serum total IgE level and body weight using the study-drug dosing table. All participants were also treated during the entire study with intranasal corticosteroids (mometasone nasal spray) as background therapy.

    Reporting group title
    Omalizumab
    Reporting group description
    		 Participants received omalizumab as a subcutaneous injection once every 2 weeks (q2w) or once every 4 weeks (q4w). The dose (from 75 mg up to 600 mg) and dosing frequency (q2w or q4w) was determined by serum total IgE level and body weight using the study-drug dosing table. All participants were also treated during the entire study with intranasal corticosteroids (mometasone nasal spray) as background therapy.

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

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    End point title
    		 Change From Baseline in Nasal Polyp Score (NPS) at Week 24
    End point description
    Total NPS ranges from 0 to 8 (sum of 0-4 for left and right nasal passage scores per the following criteria), with a lower score indicating smaller-sized nasal polyps: 0 = No polyps; 1 = Small polyps in the middle meatus not reaching below the inferior border of the middle turbinate; 2 = Polyps reaching below the lower border of the middle turbinate (modified to accommodate those with a middle turbinectomy, such that polyp must have reached the top of the inferior turbinate.); 3 = Large polyps reaching the lower border of the inferior turbinate or polyps medial to the middle turbinate; and 4 = Large polyps causing complete obstruction of the inferior nasal cavity. Two blinded primary independent expert readers reviewed every post-screening recorded video endoscopy for a given participant to determine total NPS. A third reader chose one of the two scores to be used for analysis in cases where there was any discrepancy in total NPS assigned between the two primary readers.
    End point type
    Primary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Placebo Omalizumab
    Number of subjects analysed
    65
    69
    Units: Score on a scale
        least squares mean (confidence interval 95%)
    0.06 (-0.27 to 0.38)
    -1.08 (-1.40 to -0.77)
    Statistical analysis title
    		 Change from Baseline in NPS at Week 24
    Statistical analysis description
    The primary analysis tested the null hypothesis that no treatment group difference existed for change from baseline in NPS at Week 24. As NPS and NCS are co-primary outcome measures, both null hypotheses for NPS and NCS must be rejected, with parameter estimates indicating a benefit of omalizumab over placebo, for the study to be deemed positive.
    Comparison groups
    Placebo v Omalizumab
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    P-value
    		 < 0.0001 [2]
    Method
    		 Mixed-Effect Model of Repeated Measures
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    -1.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.59
         upper limit
    		 -0.69
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.23
    Notes
    [1] - Mixed-Effect Model of Repeated Measures (MMRM) adjustments: geographic region, asthma/aspirin sensitivity, treatment, timepoint, baseline NPS, treatment and baseline NPS by timepoint interactions.
    [2] - Tested at the two-sided 0.05 significance level. There was no adjustment for multiplicity for the co-primary outcome measures.

    Primary: Change From Baseline in Average Daily Nasal Congestion Score (NCS) at Week 24

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    End point title
    		 Change From Baseline in Average Daily Nasal Congestion Score (NCS) at Week 24
    End point description
    The Nasal Congestion Score (NCS) was assessed daily by the participant via an electronic diary as the response to the following question: Is your nose blocked? The four available response options were scored from 0 (no symptoms) to 3 (severe symptoms): 0 = Not at all; 1 = Mild; 2 = Moderate; and 3 = Severe. For each study day, a score was calculated using an average of the prior 7 days among the available days within the pre-specified window (For Week 24: Study Days 155 to 186), excluding the study day itself, if a value had been recorded by the participant on at least 4 of the prior 7 days; otherwise, the 7-day prior average for that study day was to be considered missing. One calculated (non-missing) 7-day prior average was selected for analysis according to the study day with nearest proximity to Week 24 (Study Day 168), with the earlier selected in the case of a tie. Baseline was defined as the (non-missing) 7-day interval ending on the latest day prior to randomization.
    End point type
    Primary
    End point timeframe
    Baseline, Week 24 (Study Days 155 to 186)
    End point values
    		 Placebo Omalizumab
    Number of subjects analysed
    65
    70
    Units: Score on a scale
        least squares mean (confidence interval 95%)
    -0.35 (-0.56 to -0.13)
    -0.89 (-1.10 to -0.69)
    Statistical analysis title
    		 Change from Baseline in Avg Daily NCS at Week 24
    Statistical analysis description
    The primary analysis tested the null hypothesis that no treatment group difference existed for change from baseline in NCS at Week 24. As NPS and NCS are co-primary outcome measures, both null hypotheses for NPS and NCS must be rejected, with parameter estimates indicating a benefit of omalizumab over placebo, for the study to be deemed positive.
    Comparison groups
    Placebo v Omalizumab
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    		 [3]
    P-value
    		 = 0.0004 [4]
    Method
    		 Mixed-Effect Model of Repeated Measures
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    -0.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.84
         upper limit
    		 -0.25
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.15
    Notes
    [3] - Mixed-Effect Model of Repeated Measures (MMRM) adjustments: geographic region, asthma/aspirin sensitivity, treatment, timepoint, baseline NCS, treatment and baseline NCS by timepoint interactions.
    [4] - Tested at the two-sided 0.05 significance level. There was no adjustment for multiplicity for the co-primary outcome measures.

    Secondary: Change From Baseline in Average Daily Sense of Smell Score at Week 24

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    End point title
    		 Change From Baseline in Average Daily Sense of Smell Score at Week 24
    End point description
    The Sense of Smell Score was assessed daily by the participant via an electronic diary as the response to the following question: Is your sense of smell reduced? The four available response options were scored from 0 (no symptoms) to 3 (severe symptoms): 0 = Not at all; 1 = Mild; 2 = Moderate; and 3 = Severe. For each study day, a score was calculated using an average of the prior 7 days among the available days within the pre-specified window (For Week 24: Study Days 155 to 186), excluding the study day itself, if a value had been recorded by the participant on at least 4 of the prior 7 days; otherwise, the 7-day prior average for that study day was to be considered missing. One calculated (non-missing) 7-day prior average was selected for analysis according to the study day with nearest proximity to Week 24 (Study Day 168), with the earlier selected in the case of a tie. Baseline was defined as the (non-missing) 7-day interval ending on the latest day prior to randomization.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24 (Study Days 155 to 186)
    End point values
    		 Placebo Omalizumab
    Number of subjects analysed
    65
    70
    Units: Score on a scale
        least squares mean (confidence interval 95%)
    -0.23 (-0.42 to -0.04)
    -0.56 (-0.74 to -0.38)
    Statistical analysis title
    		 Change from Baseline in Avg Daily SSS at Week 24
    Statistical analysis description
    The null hypothesis was that no difference exists between the treatment groups for change from baseline in the average daily Sense of Smell Score (SSS) at Week 24.
    Comparison groups
    Placebo v Omalizumab
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0161 [5]
    Method
    		 Mixed-Effect Model of Repeated Measures
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    -0.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.6
         upper limit
    		 -0.06
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.14
    Notes
    [5] - Tested at the two-sided 0.05 significance level.

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

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    End point title
    		 Change From Baseline in Average Daily Posterior Rhinorrhea Score at Week 24
    End point description
    The Posterior Rhinorrhea Score was assessed daily by the participant via an electronic diary as the response to the following question: Do you feel dripping at the back of the nose? The four available response options were scored from 0 (no symptoms) to 3 (severe symptoms): 0=Not at all; 1=Mild; 2=Moderate; and 3=Severe. For each study day, a score was calculated using an average of the prior 7 days among available days within a pre-specified window (For Week 24: Study Days 155 to 186), excluding the study day itself, if a value had been recorded by the participant on at least 4 of the prior 7 days, otherwise the 7-day prior average for that study day was to be considered missing. One calculated (non-missing) 7-day prior average was selected for analysis according to the study day with nearest proximity to Week 24 (Study Day 168), with the earlier selected in the case of a tie. Baseline was defined as the (non-missing) 7-day interval ending on the latest day prior to randomization.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24 (Study Days 155 to 186)
    End point values
    		 Placebo Omalizumab
    Number of subjects analysed
    65
    70
    Units: Score on a scale
        least squares mean (confidence interval 95%)
    -0.16 (-0.36 to 0.04)
    -0.72 (-0.91 to -0.53)
    Statistical analysis title
    		 Change from Baseline in Avg Daily PRS at Week 24
    Statistical analysis description
    The null hypothesis was that no difference exists between the treatment groups for change from baseline in the average daily Posterior Rhinorrhea Score (PRS) at Week 24.
    Comparison groups
    Placebo v Omalizumab
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0001 [6]
    Method
    		 Mixed-Effect Model of Repeated Measures
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    -0.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.84
         upper limit
    		 -0.28
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.14
    Notes
    [6] - Tested at the two-sided 0.05 significance level.

    Secondary: Change From Baseline in Nasal Polyp Score (NPS) at Week 16

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    End point title
    		 Change From Baseline in Nasal Polyp Score (NPS) at Week 16
    End point description
    Total NPS ranges from 0 to 8 (sum of 0-4 for left and right nasal passage scores per the following criteria), with a lower score indicating smaller-sized nasal polyps: 0 = No polyps; 1 = Small polyps in the middle meatus not reaching below the inferior border of the middle turbinate; 2 = Polyps reaching below the lower border of the middle turbinate (modified to accommodate those with a middle turbinectomy, such that polyp must have reached the top of the inferior turbinate.); 3 = Large polyps reaching the lower border of the inferior turbinate or polyps medial to the middle turbinate; and 4 = Large polyps causing complete obstruction of the inferior nasal cavity. Two blinded primary independent expert readers reviewed every post-screening recorded video endoscopy for a given participant to determine total NPS. A third reader chose one of the two scores to be used for analysis in cases where there was any discrepancy in total NPS assigned between the two primary readers.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    		 Placebo Omalizumab
    Number of subjects analysed
    64
    69
    Units: Score on a scale
        least squares mean (confidence interval 95%)
    0.03 (-0.27 to 0.33)
    -0.98 (-1.27 to -0.70)
    Statistical analysis title
    		 Change from Baseline in NPS at Week 16
    Statistical analysis description
    The null hypothesis was that no difference exists between the treatment groups for change from baseline in the NPS at Week 16.
    Comparison groups
    Placebo v Omalizumab
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001 [7]
    Method
    		 Mixed-Effect Model of Repeated Measures
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    -1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.43
         upper limit
    		 -0.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.21
    Notes
    [7] - Tested at the two-sided 0.05 significance level.

    Secondary: Change From Baseline in Average Daily Nasal Congestion Score (NCS) at Week 16

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    End point title
    		 Change From Baseline in Average Daily Nasal Congestion Score (NCS) at Week 16
    End point description
    The Nasal Congestion Score (NCS) was assessed daily by the participant via an electronic diary as the response to the following question: Is your nose blocked? The four available response options, scored from 0 (no symptoms) to 3 (severe symptoms) were: 0 = Not at all; 1 = Mild; 2 = Moderate; and 3 = Severe. For each study day, a score was calculated using an average of the prior 7 days among the available days within the pre-specified window (For Week 16: Study Days 99 to 126), excluding the study day itself, if a value had been recorded by the participant on at least 4 of the prior 7 days; otherwise, the 7-day prior average for that study day was to be considered missing. One calculated (non-missing) 7-day prior average was selected for analysis according to the study day with nearest proximity to Week 24 (Study Day 112), with the earlier selected in the case of a tie. Baseline was defined as the (non-missing) 7-day interval ending on the latest day prior to randomization.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16 (Study Days 99 to 126)
    End point values
    		 Placebo Omalizumab
    Number of subjects analysed
    65
    70
    Units: Score on a scale
        least squares mean (confidence interval 95%)
    -0.32 (-0.51 to -0.13)
    -0.89 (-1.07 to -0.71)
    Statistical analysis title
    		 Change from Baseline in Avg Daily NCS at Week 16
    Statistical analysis description
    The null hypothesis was that no difference exists between the treatment groups for change from baseline in the average daily NCS at Week 16.
    Comparison groups
    Placebo v Omalizumab
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001 [8]
    Method
    		 Mixed-Effect Model of Repeated Measures
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    -0.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.83
         upper limit
    		 -0.31
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.13
    Notes
    [8] - Tested at the two-sided 0.05 significance level.

    Secondary: Change From Baseline in Participant Reported Health-Related Quality of Life (HRQoL) as Assessed by the Total Sino-Nasal Outcome Test (SNOT)-22 Questionnaire at Week 24

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    End point title
    		 Change From Baseline in Participant Reported Health-Related Quality of Life (HRQoL) as Assessed by the Total Sino-Nasal Outcome Test (SNOT)-22 Questionnaire at Week 24
    End point description
    The SNOT-22 Questionnaire, a disease specific HRQoL measure, comprises a list of 22 symptoms and social or emotional consequences of the nasal disorder. Every participant was asked to rate how severe each problem had been for them over the past 2 weeks on a scale from 0 (no problem at all) to 5 (problem as bad as it can be). The total score is the sum of the scores for all 22 items, ranging from 0 to 110, with a lower score indicating less disease and better HRQoL. A negative score indicates a decrease (or improvement) from the baseline score.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Placebo Omalizumab
    Number of subjects analysed
    65
    69
    Units: Score on a scale
        least squares mean (confidence interval 95%)
    -8.58 (-12.71 to -4.46)
    -24.70 (-28.67 to -20.73)
    Statistical analysis title
    		 Change from Baseline in SNOT-22 Score at Week 24
    Statistical analysis description
    The null hypothesis was that no difference exists between the treatment groups for change from baseline in the SNOT-22 score at Week 24.
    Comparison groups
    Placebo v Omalizumab
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001 [9]
    Method
    		 Mixed-Effect Model of Repeated Measures
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    -16.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -21.86
         upper limit
    		 -10.38
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.9
    Notes
    [9] - Tested at the two-sided 0.05 significance level.

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

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    End point title
    		 Change From Baseline in Average Daily Anterior Rhinorrhea Score at Week 24
    End point description
    The Anterior Rhinorrhea Score was assessed daily by the participant via an electronic diary as the response to the following question: Do you have a runny nose? The four available response options were scored from 0 (no symptoms) to 3 (severe symptoms): 0=Not at all; 1=Mild; 2=Moderate; and 3=Severe. For each study day, a score was calculated using an average of the prior 7 days among available days within a pre-specified window (For Week 24: Study Days 155 to 186), excluding the study day itself, if a value had been recorded by the participant on at least 4 of the prior 7 days, otherwise the 7-day prior average for that study day was to be considered missing. One calculated (non-missing) 7-day prior average was selected for analysis according to the study day with nearest proximity to Week 24 (Study Day 168), with the earlier selected in the case of a tie. Baseline was defined as the (non-missing) 7-day interval ending on the latest day prior to randomization.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24 (Study Days 155 to 186)
    End point values
    		 Placebo Omalizumab
    Number of subjects analysed
    65
    70
    Units: Score on a scale
        least squares mean (confidence interval 95%)
    -0.34 (-0.54 to -0.15)
    -0.77 (-0.96 to -0.58)
    Statistical analysis title
    		 Change from Baseline in Avg Daily ARS at Week 24
    Statistical analysis description
    The null hypothesis was that no difference exists between the treatment groups for change from baseline in the average daily Anterior Rhinorrhea Score (ARS) at Week 24.
    Comparison groups
    Placebo v Omalizumab
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0023 [10]
    Method
    		 Mixed-Effect Model of Repeated Measures
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    -0.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7
         upper limit
    		 -0.16
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.14
    Notes
    [10] - Tested at the two-sided 0.05 significance level.

    Secondary: Number of Participants Requiring Rescue Medication (Systemic Corticosteroids for ≥3 Consecutive Days) Through Week 24

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    End point title
    		 Number of Participants Requiring Rescue Medication (Systemic Corticosteroids for ≥3 Consecutive Days) Through Week 24
    End point description
    A participant was considered to have had the event of requiring rescue medication if they had taken systemic corticosteroids for 3 or more consecutive days at any point between randomization and Week 24; if the participant had greater than 155 days of follow-up on study and had not taken systemic corticosteroids for 3 or more consecutive days, then they did not have the event. Participants with less than 155 days of follow-up on the study were classified as having had the event if they discontinued study drug due to adverse event, progressive disease, or lack of efficacy and remained missing; if the participant had less than 155 days of follow-up on study and had not already met these criteria, they were classified as having a missing outcome. The null hypothesis was to be assessed by the Wald Chi-square test of the treatment term in the logistic regression model. If model convergence was an issue, then Fisher’s Exact test was to be used.
    End point type
    Secondary
    End point timeframe
    Up to Week 24
    End point values
    		 Placebo Omalizumab
    Number of subjects analysed
    65
    70
    Units: Participants
    3
    2
    Statistical analysis title
    		 Requiring Rescue Medication Through Week 24
    Statistical analysis description
    The null hypothesis was that no difference exists between the treatment groups for requirement of rescue medication through Week 24.
    Comparison groups
    Placebo v Omalizumab
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.6716 [11]
    Method
    		 Fisher exact
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.05
         upper limit
    		 5.51
    Notes
    [11] - Tested at the two-sided 0.05 significance level.

    Secondary: Number of Participants Having Had Surgery for Nasal Polyps Through Week 24

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    End point title
    		 Number of Participants Having Had Surgery for Nasal Polyps Through Week 24
    End point description
    A participant was considered to have had the event of surgery for nasal polyps if they underwent the procedure at any point between randomization and Week 24; if the participant had greater than 155 days of follow-up on study and had not undergone surgery for nasal polyps, then they did not have the event. Participants with less than 155 days of follow-up on the study were classified as having had the event if they discontinued study drug due to adverse event, progressive disease, or lack of efficacy and remained missing; if the participant had less than 155 days of follow-up on study and had not already met these criteria, they were classified as having a missing outcome. The null hypothesis was to be assessed by the Wald Chi-square test of the treatment term in the logistic regression model. If model convergence was an issue, then Fisher’s Exact test was to be used.
    End point type
    Secondary
    End point timeframe
    Up to Week 24
    End point values
    		 Placebo Omalizumab
    Number of subjects analysed
    65
    70
    Units: Participants
    1
    0
    Statistical analysis title
    		 Having Had Nasal Polypectomy Through Week 24
    Statistical analysis description
    The null hypothesis was that no difference exists between the treatment groups for having had surgery for nasal polyps through Week 24.
    Comparison groups
    Placebo v Omalizumab
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.4815 [12]
    Method
    		 Fisher exact
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 17.64
    Notes
    [12] - Tested at the two-sided 0.05 significance level.

    Secondary: Number of Participants with a Change From Baseline at Week 24 in Asthma Quality of Life Questionnaire (AQLQ) of ≥0.5 in Participants with Comorbid Asthma Only

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    End point title
    		 Number of Participants with a Change From Baseline at Week 24 in Asthma Quality of Life Questionnaire (AQLQ) of ≥0.5 in Participants with Comorbid Asthma Only
    End point description
    The AQLQ is a 32-item participant-reported measure of asthma-related quality of life (QoL) with a total score (the mean of all 32 responses) ranging from 1 (severely impaired) to 7 (not impaired at all); a higher score indicates a better QoL. An increase of at least 0.5 points in the AQLQ score was considered the minimal important difference for improvement in QoL. The analysis was conducted only in the subgroup of participants with comorbid asthma at screening and AQLQ assessments at Baseline and Week 24.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Placebo Omalizumab
    Number of subjects analysed
    31
    37
    Units: Participants
    9
    20
    Statistical analysis title
    		 Change from Baseline in AQLQ of ≥0.5 at Week 24
    Statistical analysis description
    The null hypothesis was that no difference exists between the treatment groups for number of participants with a change from baseline in AQLQ score of ≥0.5 at Week 24.
    Comparison groups
    Placebo v Omalizumab
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0492
    Method
    		 Wald Chi-Square
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1
         upper limit
    		 13.71

    Secondary: Number of Participants Requiring Rescue Treatment (Systemic Corticosteroids For ≥3 Consecutive Days or Having Had Surgery for Nasal Polyps) Through Week 24

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    End point title
    		 Number of Participants Requiring Rescue Treatment (Systemic Corticosteroids For ≥3 Consecutive Days or Having Had Surgery for Nasal Polyps) Through Week 24
    End point description
    A participant was considered to have had the event of requiring rescue treatment if they had taken systemic corticosteroids for 3 or more consecutive days or had nasal polypectomy at any point between randomization and Week 24; if the participant had greater than 155 days of follow-up on study and had not received rescue treatment, then they did not have the event. Participants with less than 155 days of follow-up on the study were classified as having had the event if they discontinued study drug due to adverse event, progressive disease, or lack of efficacy and remained missing; if the participant had less than 155 days of follow-up on study and had not already met these criteria, they were classified as having a missing outcome. The null hypothesis was to be assessed by the Wald Chi-square test of the treatment term in the logistic regression model. If model convergence was an issue, then Fisher’s Exact test was to be used.
    End point type
    Secondary
    End point timeframe
    Up to Week 24
    End point values
    		 Placebo Omalizumab
    Number of subjects analysed
    65
    70
    Units: Participants
    3
    2
    Statistical analysis title
    		 Requiring Rescue Treatment Through Week 24
    Statistical analysis description
    The null hypothesis was that no difference exists between the treatment groups for requirement of rescue treatment through Week 24.
    Comparison groups
    Placebo v Omalizumab
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.6716 [13]
    Method
    		 Fisher exact
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.05
         upper limit
    		 5.51
    Notes
    [13] - Tested at the two-sided 0.05 significance level.

    Secondary: Number of Participants With Reduction in the Need for Surgery for Nasal Polyps by Week 24, as Defined by an NPS of ≤4 (Unilateral Score of ≤2 on Each Side) and Improvement in SNOT-22 Score of ≥8.9

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    End point title
    		 Number of Participants With Reduction in the Need for Surgery for Nasal Polyps by Week 24, as Defined by an NPS of ≤4 (Unilateral Score of ≤2 on Each Side) and Improvement in SNOT-22 Score of ≥8.9
    End point description
    A participant was considered to have had the event of reduction in the need for surgery for nasal polyps if they had a Nasal Polyp Score (NPS) of ≤4 and an improvement in the SNOT-22 score of ≥8.9 (minimal important difference) without rescue treatment at Week 24; if the participant had received rescue treatment or had discontinued study drug due to adverse event, progressive disease, or lack of efficacy and remained missing, then they did not have the event. Participants without an intercurrent event and without valid Week 24 assessments of both NPS and SNOT-22 were classified as having a missing outcome. The null hypothesis was to be assessed by the Wald Chi-square test of the treatment term in the logistic regression model. If model convergence was an issue, then Fisher’s Exact test was to be used.
    End point type
    Secondary
    End point timeframe
    Up to Week 24
    End point values
    		 Placebo Omalizumab
    Number of subjects analysed
    65
    69
    Units: Participants
    2
    13
    Statistical analysis title
    		 Reduction in Need for Nasal Polypectomy by Week 24
    Statistical analysis description
    The null hypothesis was that no difference exists between the treatment groups for change from baseline in reduction in the need for surgery for nasal polyps by Week 24.
    Comparison groups
    Placebo v Omalizumab
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0209 [14]
    Method
    		 Wald Chi-Square
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    6.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.32
         upper limit
    		 29.6
    Notes
    [14] - Tested at the two-sided 0.05 significance level.

    Secondary: Change From Baseline in Average Daily Total Nasal Symptom Score (TNSS) at Week 24

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    End point title
    		 Change From Baseline in Average Daily Total Nasal Symptom Score (TNSS) at Week 24
    End point description
    The Total Nasal Symptom Score (TNSS) was defined as the sum of the four individual scores for Nasal Congestion Score, Anterior Rhinorrhea Score, Posterior Rhinorrhea Score, and Sense of Smell Score, ranging from 0 (no symptoms) to 12 (most severe symptoms), assessed daily by the participant via an electronic diary. For each study day, a score was calculated using an average of the prior 7 days among the available days within the pre-specified window (For Week 24: Study Days 155 to 186), excluding the study day itself, if a value had been recorded by the participant on at least 4 of the prior 7 days; otherwise, the 7-day prior average for that study day was to be considered missing. One calculated (non-missing) 7-day prior average was selected for analysis according to the study day with nearest proximity to Week 24 (Study Day 168), with the earlier selected in the case of a tie. Baseline was defined as the (non-missing) 7-day interval ending on the latest day prior to randomization.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24 (Study Days 155 to 186)
    End point values
    		 Placebo Omalizumab
    Number of subjects analysed
    65
    70
    Units: Score on a scale
        least squares mean (confidence interval 95%)
    -1.06 (-1.74 to -0.38)
    -2.97 (-3.61 to -2.32)
    Statistical analysis title
    		 Change from Baseline in Avg Daily TNSS at Week 24
    Statistical analysis description
    The null hypothesis was that no difference exists between the treatment groups for change from baseline in the average daily Total Nasal Symptom Score (TNSS) at Week 24.
    Comparison groups
    Placebo v Omalizumab
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0001 [15]
    Method
    		 Mixed-Effect Model of Repeated Measures
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    -1.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.85
         upper limit
    		 -0.96
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.48
    Notes
    [15] - Tested at the two-sided 0.05 significance level.

    Secondary: Change From Baseline in Sense of Smell, as Assessed by The University of Pennsylvania Smell Identification Test (UPSIT) at Week 24

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    End point title
    		 Change From Baseline in Sense of Smell, as Assessed by The University of Pennsylvania Smell Identification Test (UPSIT) at Week 24
    End point description
    The UPSIT is a 40-question instrument that measures an individual’s ability to detect odors and ranges from 0 to 40, with a higher score indicating a better sense of smell. It is a self-administered "scratch-and-sniff" test provided in booklets that have 40 microencapsulated odorants, each with a multiple-choice option for the response. The number of correct responses is summed to provide a total score.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Placebo Omalizumab
    Number of subjects analysed
    61
    67
    Units: Score on a scale
        least squares mean (confidence interval 95%)
    0.63 (-1.12 to 2.39)
    4.44 (2.77 to 6.12)
    Statistical analysis title
    		 Change from Baseline in UPSIT Score at Week 24
    Statistical analysis description
    The null hypothesis was that no difference exists between the treatment groups for change from baseline in the UPSIT score at Week 24.
    Comparison groups
    Placebo v Omalizumab
    Number of subjects included in analysis
    128
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0024 [16]
    Method
    		 Mixed-Effect Model of Repeated Measures
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    3.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.38
         upper limit
    		 6.24
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.23
    Notes
    [16] - Tested at the two-sided 0.05 significance level.

    Secondary: Number of Participants who Experienced at Least One Adverse Event by Greatest Severity

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    End point title
    		 Number of Participants who Experienced at Least One Adverse Event by Greatest Severity
    End point description
    All adverse events (AE) were treatment emergent AEs, defined as any new AE or any worsening of an existing condition with an onset date on or after the first study drug administration date. AEs were assessed for severity according to the following grading scale: mild (discomfort noticed, but no disruption of normal daily activity), moderate (discomfort sufficient to reduce or affect normal daily activity), or severe (incapacitating with inability to work or to perform normal daily activity). The terms "severe" and "serious" are not synonymous; regardless of severity, some events may have also met seriousness criteria. Multiple occurrences of the same AE in one individual are counted once at the greatest intensity.
    End point type
    Secondary
    End point timeframe
    Up to Week 28
    End point values
    		 Placebo Omalizumab
    Number of subjects analysed
    66
    72
    Units: Participants
        AEs of Any Severity
    41
    36
        Mild AEs
    20
    15
        Moderate AEs
    18
    20
        Severe AEs
    3
    1
    No statistical analyses for this end point

    Secondary: Number of Participants who Experienced at Least One Serious Adverse Event

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    End point title
    		 Number of Participants who Experienced at Least One Serious Adverse Event
    End point description
    A serious adverse event was defined as any adverse event that met any of the following criteria: was fatal; was life-threatening; required or prolonged inpatient hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the study drug; or, was a significant medical event in the investigator's judgment. Multiple occurrences of the same serious adverse event in one individual were counted once.
    End point type
    Secondary
    End point timeframe
    Up to Week 28
    End point values
    		 Placebo Omalizumab
    Number of subjects analysed
    66
    72
    Units: Participants
    1
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Adverse Events Leading to Omalizumab/Placebo Discontinuation

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    End point title
    		 Number of Participants With Adverse Events Leading to Omalizumab/Placebo Discontinuation
    End point description
    End point type
    Secondary
    End point timeframe
    Up to Week 24
    End point values
    		 Placebo Omalizumab
    Number of subjects analysed
    66
    72
    Units: Participants
    1
    0
    No statistical analyses for this end point

    Secondary: Number of Participants with Laboratory Abnormalities by Highest Grade Post-Baseline

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    End point title
    		 Number of Participants with Laboratory Abnormalities by Highest Grade Post-Baseline
    End point description
    Clinical laboratory tests for serum chemistry and hematology parameters were performed at laboratories; any abnormal values (High or Low) were based on laboratory normal ranges. Laboratory abnormalities are presented by the highest grade according to the World Health Organization (WHO) grade for Adverse Events, except for eosinophils and white blood cells that were graded according to the FDA Toxicity Grading Scale for Healthy Volunteers. Not every abnormal laboratory value qualified as an adverse event, only if it met any of the following criteria: clinically significant (per investigator); accompanied by clinical symptoms; resulted in a change in study treatment; or required a change in concomitant therapy. SGPT/ALT = serum glutamic-pyruvic transaminase/alanine aminotransferase; SGOT/AST = serum glutamic-oxaloacetic transaminase/aspartate aminotransferase
    End point type
    Secondary
    End point timeframe
    Up to Week 28
    End point values
    		 Placebo Omalizumab
    Number of subjects analysed
    66
    72
    Units: Participants
        Alkaline Phosphatase-High, Any Grade(Gr.)(n=65,72)
    0
    2
        Alkaline Phosphatase - High, Gr. 1 (n=65,72)
    0
    2
        SGPT/ALT - High, Any Gr. (n=65,72)
    5
    4
        SGPT/ALT - High, Gr. 1 (n=65,72)
    5
    3
        SGPT/ALT - High, Gr. 3 (n=65,72)
    0
    1
        SGOT/AST - High, Any Gr. (n=64,70)
    1
    2
        SGOT/AST - High, Gr. 1 (n=64,70)
    1
    0
        SGOT/AST - High, Gr. 2 (n=64,70)
    0
    2
        Creatinine - High, Any Gr. (n=65,72)
    0
    0
        Eosinophils, Abs. - High, Any Gr. (n=65,72)
    12
    8
        Eosinophils, Abs. - High, Gr. 1 (n=65,72)
    12
    7
        Eosinophils, Abs. - High, Gr. 2 (n=65,72)
    0
    1
        Hemoglobin - Low, Any Gr. (n=65,72)
    0
    0
        Hemoglobin - High, Any Gr. (n=65,72)
    0
    0
        Neutrophils, Segmented(Abs.)-Low, Any Gr.(n=65,72)
    8
    4
        Neutrophils, Segmented(Abs.)-Low, Gr. 1 (n=65,72)
    5
    3
        Neutrophils, Segmented(Abs.)-Low, Gr. 2 (n=65,72)
    3
    1
        Platelet - Low, Any Gr. (n=65,72)
    0
    0
        Potassium - Low, Any Gr. (n=65,72)
    0
    0
        Potassium - High, Any Gr. (n=65,72)
    3
    0
        Potassium - High, Gr. 1 (n=65,72)
    3
    0
        Sodium - Low, Any Gr. (n=65,72)
    0
    0
        Sodium - High, Any Gr. (n=65,72)
    4
    2
        Sodium - High, Gr. 1 (n=65,72)
    4
    2
        Bilirubin - High, Any Gr. (n=65,66)
    1
    3
        Bilirubin - High, Gr. 1 (n=65,66)
    1
    1
        Bilirubin - High, Gr. 2 (n=65,66)
    0
    2
        Total Leukocyte Count - Low, Any Gr. (n=65,72)
    4
    1
        Total Leukocyte Count - Low, Gr. 1 (n=65,72)
    4
    1
        Total Leukocyte Count - High, Any Gr. (n=65,72)
    4
    3
        Total Leukocyte Count - High, Gr. 1 (n=65,72)
    4
    3
    No statistical analyses for this end point

    Secondary: Mean Serum Concentration of Omalizumab at Specified Timepoints

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    End point title
    		 Mean Serum Concentration of Omalizumab at Specified Timepoints
    End point description
    Serum concentrations of omalizumab were quantified using an enzyme-linked immunoabsorbent assay (ELISA) with a lower limit of quantification (LLOQ) of 28.0 nanograms per millilitre (ng/mL). According to the analysis plan, values below the lower limit of quantification (BLQ) were set to 14 ng/mL (i.e. half of LLOQ value). If one-third or fewer of participants had results that were BLQ, then all summary statistics were to be calculated. However, if more than one-third of participants had results that were BLQ, then the mean and standard deviation were non-reportable and only the median and maximum were to be calculated for that timepoint. The value '9999999' indicates that per the analysis plan, the mean and standard deviation at Day 1 (before dosing) were non-reportable because more than one-third of participants (all except for 3) had results that were below the lower limit of quantification.
    End point type
    Secondary
    End point timeframe
    Predose on Day 1, Week 16, Week 24, Unscheduled Visit (outside of planned study visits, as clinically indicated), Dosing Termination/Early Termination Visit (up to 28 weeks)
    End point values
    		 Placebo Omalizumab
    Number of subjects analysed
    0 [17]
    72
    Units: nanograms per millilitre (ng/mL)
    arithmetic mean (standard deviation)
        Day 1 (n=0,71)
    ±
    9999999 ± 9999999
        Week 16 (n=0,65)
    ±
    29000 ± 22000
        Week 24 (n=0,69)
    ±
    31200 ± 23900
        Unscheduled Visit (n=0,2)
    ±
    6140 ± 1390
        Dosing Termination/Early Termination Visit (n=0,3)
    ±
    7490 ± 4510
    Notes
    [17] - Only omalizumab-treated participants at each timepoint were included in this analysis.
    No statistical analyses for this end point

    Secondary: Median Serum Concentration of Omalizumab at Specified Timepoints

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    End point title
    		 Median Serum Concentration of Omalizumab at Specified Timepoints
    End point description
    Serum concentrations of omalizumab were quantified using an enzyme-linked immunoabsorbent assay (ELISA) with a lower limit of quantification (LLOQ) of 28.0 nanograms per millilitre (ng/mL). According to the analysis plan, values below the lower limit of quantification (BLQ) were set to 14 ng/mL (i.e. half of LLOQ value). If one-third or fewer of participants had results that were BLQ, then all summary statistics were to be calculated. However, if more than one-third of participants had results that were BLQ, then the mean and standard deviation were non-reportable and only the median and maximum were to be calculated for that timepoint. The value '-9999999' indicates that per the analysis plan, the minimum at Day 1 (before dosing) was non-reportable because more than one-third of participants (all except for 3) had results that were below the lower limit of quantification.
    End point type
    Secondary
    End point timeframe
    Predose on Day 1, Week 16, Week 24, Unscheduled Visit (outside of planned study visits, as clinically indicated), Dosing Termination/Early Termination Visit (up to 28 weeks)
    End point values
    		 Placebo Omalizumab
    Number of subjects analysed
    0 [18]
    72
    Units: nanograms per millilitre (ng/mL)
    median (full range (min-max))
        Day 1 (n=0,71)
    ( to )
    0.00 (-9999999 to 368)
        Week 16 (n=0,65)
    ( to )
    23100 (5280 to 108000)
        Week 24 (n=0,69)
    ( to )
    24700 (5920 to 125000)
        Unscheduled Visit (n=0,2)
    ( to )
    6140 (5150 to 7120)
        Dosing Termination/Early Termination Visit (n=0,3)
    ( to )
    9430 (2340 to 10700)
    Notes
    [18] - Only omalizumab-treated participants at each timepoint were included in this analysis.
    No statistical analyses for this end point

    Secondary: Mean Serum Concentration of Total and Free Immunoglobulin E (IgE) at Specified Timepoints

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    End point title
    		 Mean Serum Concentration of Total and Free Immunoglobulin E (IgE) at Specified Timepoints
    End point description
    Serum concentrations of total immunoglobulin E (IgE) and free IgE were measured throughout the 24-week blinded treatment period, as target engagement biomarkers of omalizumab, using validated quantitative immunoassays with lower limits of quantification of 2 and 0.83 International Units per millilitre (IU/mL), respectively, and upper limits of quantification (ULQ) of 5000 and 62.5 IU/mL, respectively. The free IgE assay had limited range to measure circulating levels of free IgE in the presence of complexes of omalizumab-IgE. According to the analysis plan for the free IgE assay, results above ULQ were set to 62.5 IU/mL. If results for one-third or fewer of participants were greater than (>) the ULQ, then all summary statistics were to be reported. However, if results for more than one-third of participants were >ULQ, then only the median, interquartile range and minimum were calculated, and the mean, standard deviation, and maximum were non-reportable (as indicated by '999999').
    End point type
    Secondary
    End point timeframe
    Predose on Day 1, Week 16, Week 24
    End point values
    		 Placebo Omalizumab
    Number of subjects analysed
    66
    72
    Units: IU/mL
    arithmetic mean (standard deviation)
        Total IgE - Day 1 (n=65,69)
    187 ± 164
    168 ± 169
        Total IgE - Week 16 (n=62,68)
    189 ± 165
    604 ± 368
        Total IgE - Week 24 (n=61,69)
    182 ± 164
    594 ± 340
        Free IgE - Day 1 (n=65,71)
    999999 ± 999999
    999999 ± 999999
        Free IgE - Week 16 (n=63,68)
    999999 ± 999999
    10.0 ± 8.39
        Free IgE - Week 24 (n=63,68)
    999999 ± 999999
    9.16 ± 8.91
    No statistical analyses for this end point

    Secondary: Median Serum Concentration of Total and Free Immunoglobulin E (IgE) at Specified Timepoints

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    End point title
    		 Median Serum Concentration of Total and Free Immunoglobulin E (IgE) at Specified Timepoints
    End point description
    Serum concentrations of total immunoglobulin E (IgE) and free IgE were measured throughout the 24-week blinded treatment period, as target engagement biomarkers of omalizumab, using validated quantitative immunoassays with lower limits of quantification of 2 and 0.83 International Units per millilitre (IU/mL), respectively, and upper limits of quantification (ULQ) of 5000 and 62.5 IU/mL, respectively. The free IgE assay had limited range to measure circulating levels of free IgE in the presence of complexes of omalizumab-IgE. According to the analysis plan for the free IgE assay, results above ULQ were set to 62.5 IU/mL. If results for one-third or fewer of the participants were greater than the ULQ, then all summary statistics were to be reported. However, if the results for more than one-third of participants were greater than the ULQ, then only the median, interquartile range and minimum were calculated, and the mean, standard deviation, and maximum were non-reportable.
    End point type
    Secondary
    End point timeframe
    Predose on Day 1, Week 16, Week 24
    End point values
    		 Placebo Omalizumab
    Number of subjects analysed
    66
    72
    Units: IU/mL
    median (inter-quartile range (Q1-Q3))
        Total IgE - Day 1 (n=65,69)
    165 (79.0 to 221)
    121 (70.0 to 210)
        Total IgE - Week 16 (n=62,68)
    138 (71.0 to 248)
    505 (351 to 730)
        Total IgE - Week 24 (n=61,69)
    143 (78.0 to 237)
    498 (325 to 845)
        Free IgE - Day 1 (n=65,71)
    62.5 (35.0 to 62.5)
    62.5 (48.3 to 62.5)
        Free IgE - Week 16 (n=63,68)
    62.5 (32.3 to 62.5)
    7.85 (5.63 to 12.2)
        Free IgE - Week 24 (n=63,68)
    62.5 (30.5 to 62.5)
    7.02 (4.88 to 10.2)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Baseline until end of safety follow-up (up to 28 weeks)
    Adverse event reporting additional description
    The safety analysis set consisted of all participants who received at least one dose of study drug, grouped according to treatment received during the treatment period.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Omalizumab
    Reporting group description
    		 Participants received omalizumab as a subcutaneous injection once every 2 weeks (q2w) or once every 4 weeks (q4w). The dose (from 75 mg up to 600 mg) and dosing frequency (q2w or q4w) was determined by serum total IgE level and body weight using the study-drug dosing table. All participants were also treated during the entire study with intranasal corticosteroids (mometasone nasal spray) as background therapy.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received matching placebo as a subcutaneous injection once every 2 weeks or once every 4 weeks. The dose and dosing frequency was determined by serum total IgE level and body weight using the study-drug dosing table. All participants were also treated during the entire study with intranasal corticosteroids (mometasone nasal spray) as background therapy.

    Serious adverse events
    		 Omalizumab Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 66 (1.52%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Omalizumab Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 72 (16.67%)
    16 / 66 (24.24%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 72 (5.56%)
    4 / 66 (6.06%)
         occurrences all number
    5
    5
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    3 / 72 (4.17%)
    10 / 66 (15.15%)
         occurrences all number
    4
    12
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 72 (2.78%)
    4 / 66 (6.06%)
         occurrences all number
    2
    4
    Infections and infestations
    Sinusitis
         subjects affected / exposed
    4 / 72 (5.56%)
    1 / 66 (1.52%)
         occurrences all number
    4
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Oct 2017
    The key changes in Protocol version 2 are summarized: -An additional exclusion criterion was added to exclude subjects with a history of myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack or a known history of a hypercoagulable disorder.; -The inclusion criteria were updated to specify acceptable methods of contraception. Barrier methods with use of spermicides allowed under Protocol version 1 were not permitted and acceptable methods included surgical sterilization, hormonal contraception, and intrauterine device. Also, four additional urine pregnancy tests were added to the treatment period.; -Viral serologies for HIV, hepatitis B, and hepatitis C were added during screening at Day -35.; -Additional specifications were added to the section on the management of subjects who experienced specific AEs. While liver injury had not been described as a risk associated with omalizumab, this new section specified how study drug should be managed for subjects who experienced drug induced liver injury.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

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