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    Clinical Trial Results:
    A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study to Evaluate the Efficacy and Safety of Xolair (Omalizumab) in Patients With Chronic Idiopathic Urticaria (CIU) Who Remain Symptomatic Despite Antihistamine Treatment (H1)

    Summary
    EudraCT number
    		 2010-022782-99
    Trial protocol
    		 FR   DE   DK   IT   ES  
    Global end of trial date
    17 Oct 2012

    Results information
    Results version number
    		 v1
    This version publication date
    15 Jul 2016
    First version publication date
    08 Aug 2015
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    GA00887 (Q4881g)
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01287117
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124., Basel, Switzerland, CH-4070
    Public contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +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
    17 Oct 2012
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Oct 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This was a global, Phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of omalizumab administered subcutaneously as an add-on therapy for the treatment of adolescent and adult participants aged 12 to 75 years who have been diagnosed with refractory CIU and who remain symptomatic despite standard dosed H1 antihistamine treatment.
    Protection of trial subjects
    This study was conducted in accordance with the U.S. Food and Drug Administration (FDA) regulations, the International Conference on Harmonisation (ICH) E6 Guideline for Good Clinical Practice (GCP), Declaration of Helsinki, and applicable local, state, and federal laws, as well as other applicable country laws. The Clinical Study Protocol (CSP) and the Informed Consent Forms (ICFs) were reviewed and approved by an Independent Ethics Committee (IEC).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Feb 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 17
    Country: Number of subjects enrolled
    France: 9
    Country: Number of subjects enrolled
    Germany: 26
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Poland: 39
    Country: Number of subjects enrolled
    Turkey: 2
    Country: Number of subjects enrolled
    United States: 220
    Country: Number of subjects enrolled
    Spain: 4
    Worldwide total number of subjects
    319
    EEA total number of subjects
    97
    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)
    18
    Adults (18-64 years)
    285
    From 65 to 84 years
    16
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Randomized population: All randomized participants regardless of whether they received any study drug.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants received placebo subcutaneously every 4 weeks during the 24-week double-blind treatment period.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for cutaneous solution
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received placebo administered by SC injection every 4 weeks during the 24-week double-blind treatment period.

    Arm title
    		 Omalizumab 75 mg
    Arm description
    		 Participants received omalizumab 75 milligrams (mg) subcutaneously every 4 weeks during the 24-week double-blind treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Omalizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for cutaneous solution
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received SC omalizumab at doses of 75, 150, or 300 mg every 4 weeks during the 24-week, double-blind treatment period.

    Arm title
    		 Omalizumab 150 mg
    Arm description
    		 Participants received omalizumab 150 mg subcutaneously every 4 weeks during the 24-week double-blind treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Omalizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for cutaneous solution
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received SC omalizumab at doses of 75, 150, or 300 mg every 4 weeks during the 24-week, double-blind treatment period.

    Arm title
    		 Omalizumab 300 mg
    Arm description
    		 Participants received omalizumab 300 mg subcutaneously every 4 weeks during the 24-week double-blind treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Omalizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for cutaneous solution
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received SC omalizumab at doses of 75, 150, or 300 mg every 4 weeks during the 24-week, double-blind treatment period.

    Number of subjects in period 1
    		Placebo Omalizumab 75 mg Omalizumab 150 mg Omalizumab 300 mg
    Started
    80
    78
    80
    81
    Received Treatment
    80
    77
    80
    81
    Completed
    65
    64
    64
    69
    Not completed
    15
    14
    16
    12
         Physician decision
    -
    1
    1
    1
         Disease progression
    10
    5
    6
    5
         Adverse event, non-fatal
    2
    1
    1
    1
         Lost to follow-up
    1
    1
    -
    -
         Participant/Legal Guardian's decision
    2
    6
    8
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo subcutaneously every 4 weeks during the 24-week double-blind treatment period.

    Reporting group title
    Omalizumab 75 mg
    Reporting group description
    		 Participants received omalizumab 75 milligrams (mg) subcutaneously every 4 weeks during the 24-week double-blind treatment period.

    Reporting group title
    Omalizumab 150 mg
    Reporting group description
    		 Participants received omalizumab 150 mg subcutaneously every 4 weeks during the 24-week double-blind treatment period.

    Reporting group title
    Omalizumab 300 mg
    Reporting group description
    		 Participants received omalizumab 300 mg subcutaneously every 4 weeks during the 24-week double-blind treatment period.

    Reporting group values
    		 Placebo Omalizumab 75 mg Omalizumab 150 mg Omalizumab 300 mg Total
    Number of subjects
    		 80 78 80 81 319
    Age categorical
    Units: Subjects
    Age continuous
    Modified Intent-to-Treat (mITT) Population: All participants randomized in the study who received at least 1 dose of study drug. One participant (randomized to omalizumab 75 mg) did not receive study drug and was not included in the mITT Population.
    Units: years
        arithmetic mean (standard deviation)
    		 40.4 ( 15.6 ) 41.1 ( 15.6 ) 41.1 ( 14 ) 42.4 ( 13.2 ) -
    Gender categorical
    Units: Subjects
        Female
    		 52 56 64 60 232
        Male
    		 28 22 16 21 87

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo subcutaneously every 4 weeks during the 24-week double-blind treatment period.

    Reporting group title
    Omalizumab 75 mg
    Reporting group description
    		 Participants received omalizumab 75 milligrams (mg) subcutaneously every 4 weeks during the 24-week double-blind treatment period.

    Reporting group title
    Omalizumab 150 mg
    Reporting group description
    		 Participants received omalizumab 150 mg subcutaneously every 4 weeks during the 24-week double-blind treatment period.

    Reporting group title
    Omalizumab 300 mg
    Reporting group description
    		 Participants received omalizumab 300 mg subcutaneously every 4 weeks during the 24-week double-blind treatment period.

    Primary: Change From Baseline to Week 12 in the Weekly Itch Severity Score

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    End point title
    		 Change From Baseline to Week 12 in the Weekly Itch Severity Score
    End point description
    The weekly itch severity score is the sum of the daily itch severity scores over 7 days and ranges from 0 to 21. The daily itch severity score is the average of the morning and evening scores on a scale of 0 (none) to 3 (severe). The Baseline weekly itch severity score is the sum of the daily itch severity scores over the 7 days prior to the first treatment. A higher itch severity score indicates more severe itching. A negative change score indicates improvement. mITT Population: All randomized participants who received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo Omalizumab 75 mg Omalizumab 150 mg Omalizumab 300 mg
    Number of subjects analysed
    80
    77
    80
    81
    Units: units on a scale
    arithmetic mean (standard deviation)
        Change From Baseline to Week 12 in the Weekly Itch
    -3.63 ( 5.22 )
    -6.46 ( 6.14 )
    -6.66 ( 6.28 )
    -9.4 ( 5.73 )
    Statistical analysis title
    		 Change From Baseline to Week 12 in the Weekly Itch
    Statistical analysis description
    The null hypothesis was that there was no difference between the placebo and the omalizumab 75 mg groups.
    Comparison groups
    Omalizumab 75 mg v Placebo
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.001 [2]
    Method
    		 ANCOVA
    Parameter type
    		 Least squares mean difference
    Point estimate
    -2.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.71
         upper limit
    		 -1.21
    Notes
    [1] - Covariates included in the analysis were baseline weekly itch severity score (less than [<] 13 verses [vs] ≥ 13) and baseline weight (< 80 kg vs ≥ 80 kg).
    [2] - A multiplicity type I error control plan was employed to adjust for the comparison of multiple omalizumab groups to the placebo group in order to maintain an overall type I error rate of 0.05 (2-sided).
    Statistical analysis title
    		 Change From Baseline to Week 12 in the Weekly Itch
    Statistical analysis description
    The null hypothesis was that there was no difference between the placebo and the omalizumab 150 mg groups.
    Comparison groups
    Placebo v Omalizumab 150 mg
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.0012 [4]
    Method
    		 ANCOVA
    Parameter type
    		 Least squares mean difference
    Point estimate
    -2.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.72
         upper limit
    		 -1.18
    Notes
    [3] - Covariates included in the analysis were baseline weekly itch severity score (<13 vs ≥13) and baseline weight (<80 kg vs ≥80 kg).
    [4] - A multiplicity type I error control plan was employed to adjust for the comparison of multiple omalizumab groups to the placebo group in order to maintain an overall type I error rate of 0.05 (2-sided).
    Statistical analysis title
    		 Change From Baseline to Week 12 in the Weekly Itch
    Statistical analysis description
    The null hypothesis was that there was no difference between the placebo and the omalizumab 300 mg groups.
    Comparison groups
    Placebo v Omalizumab 300 mg
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.0001 [6]
    Method
    		 ANCOVA
    Parameter type
    		 Least squares mean difference
    Point estimate
    -5.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.49
         upper limit
    		 -4.1
    Notes
    [5] - Covariates included in the analysis were baseline weekly itch severity score (<13 vs ≥13) and baseline weight (<80 kg vs ≥80 kg).
    [6] - A multiplicity type I error control plan was employed to adjust for the comparison of multiple omalizumab groups to the placebo group in order to maintain an overall type I error rate of 0.05 (2-sided).

    Secondary: Change From Baseline to Week 12 in the Urticaria Activity Score Over 7 Days (UAS7)

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    End point title
    		 Change From Baseline to Week 12 in the Urticaria Activity Score Over 7 Days (UAS7)
    End point description
    The UAS7 is the sum of the daily urticarial activity scores over 7 days and ranges from 0 to 42. The daily urticarial activity score is the average of the morning and evening urticarial activity scores and ranges from 0 to 6. The urticarial activity score is the sum of ratings on a scale of 0 to 3 (0 is equal to [=] none to 3 = intense/severe) for (1) the number of wheals (hives) and (2) itch intensity over the previous 12 hours, ranges from 0 to 6, and is measured twice daily (morning and evening). The Baseline score is the sum of the daily urticarial activity scores over the 7 days prior to the first treatment. A higher urticarial activity score indicates more urticaria activity. A negative change score indicates improvement. mITT Population: All randomized participants who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo Omalizumab 75 mg Omalizumab 150 mg Omalizumab 300 mg
    Number of subjects analysed
    80
    77
    80
    81
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Change From Baseline to Week 12 in the UAS7
    -8.01 ( 11.47 )
    -13.82 ( 13.26 )
    -14.44 ( 12.95 )
    -20.75 ( 12.17 )
    Statistical analysis title
    		 Change From Baseline to Week 12 in the UAS7
    Statistical analysis description
    The null hypothesis was that there was no difference between the placebo and the omalizumab 75 mg groups.
    Comparison groups
    Placebo v Omalizumab 75 mg
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.0035 [8]
    Method
    		 ANCOVA
    Parameter type
    		 Least squares mean difference
    Point estimate
    -5.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.59
         upper limit
    		 -1.92
    Notes
    [7] - Covariates included in the analysis were baseline UAS7 (< median vs ≥ median) and baseline weight (<80 kg vs ≥80 kg).
    [8] - A pre-specified hierarchical order of testing was employed to adjust for the comparison of multiple omalizumab groups to the placebo group in order to maintain an overall type I error rate of 0.05 (2-sided) within each dose.
    Statistical analysis title
    		 Change From Baseline to Week 12 in the UAS7
    Statistical analysis description
    The null hypothesis was that there was no difference between the placebo and the omalizumab 150 mg groups.
    Comparison groups
    Placebo v Omalizumab 150 mg
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 = 0.0008 [10]
    Method
    		 ANCOVA
    Parameter type
    		 Least squares mean difference
    Point estimate
    -6.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.33
         upper limit
    		 -2.75
    Notes
    [9] - Covariates included in the analysis were baseline UAS7 (< median vs ≥ median) and baseline weight (<80 kg vs ≥80 kg).
    [10] - A pre-specified hierarchical order of testing was employed to adjust for the comparison of multiple omalizumab groups to the placebo group in order to maintain an overall type I error rate of 0.05 (2-sided) within each dose.
    Statistical analysis title
    		 Change From Baseline to Week 12 in the UAS7
    Statistical analysis description
    The null hypothesis was that there was no difference between the placebo and the omalizumab 300 mg groups.
    Comparison groups
    Placebo v Omalizumab 300 mg
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.0001 [12]
    Method
    		 ANCOVA
    Parameter type
    		 Least squares mean difference
    Point estimate
    -12.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.44
         upper limit
    		 -9.16
    Notes
    [11] - Covariates included in the analysis were baseline UAS7 (< median vs ≥ median) and baseline weight (<80 kg vs ≥80 kg).
    [12] - A pre-specified hierarchical order of testing was employed to adjust for the comparison of multiple omalizumab groups to the placebo group in order to maintain an overall type I error rate of 0.05 (2-sided) within each dose.

    Secondary: Change From Baseline to Week 12 in the Weekly Number of Hives Score

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    End point title
    		 Change From Baseline to Week 12 in the Weekly Number of Hives Score
    End point description
    The weekly hives score is the sum of the daily hives scores over 7 days and ranges from 0 to 21. The number of hives is measured twice daily (morning and evening) on a scale of 0 (none) to 3 (> 12 hives per 12 hours). The daily hives score is the average of the morning and evening scores. The Baseline score is the sum of the daily hives scores over the 7 days prior to the first treatment. A higher score indicates more hives. A negative change score indicates improvement. mITT Population: All randomized participants who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo Omalizumab 75 mg Omalizumab 150 mg Omalizumab 300 mg
    Number of subjects analysed
    80
    77
    80
    81
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -4.37 ( 6.6 )
    -7.36 ( 7.52 )
    -7.78 ( 7.08 )
    -11.35 ( 7.25 )
    Statistical analysis title
    		 Change From Baseline in Hives Score at Week 12
    Statistical analysis description
    The null hypothesis was that there was no difference between the placebo and the omalizumab 75 mg groups.
    Comparison groups
    Placebo v Omalizumab 75 mg
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 = 0.0149 [14]
    Method
    		 ANCOVA
    Parameter type
    		 Least squares mean difference
    Point estimate
    -2.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.95
         upper limit
    		 -0.54
    Notes
    [13] - Covariates included in the analysis were baseline weekly number of hives score (< median vs ≥ median) and baseline weight (< 80 kg vs ≥ 80 kg).
    [14] - A pre-specified hierarchical order of testing was employed to adjust for the comparison of multiple omalizumab groups to the placebo group in order to maintain an overall type I error rate of 0.05 (2-sided) within each dose.
    Statistical analysis title
    		 Change From Baseline in Hives Score at Week 12
    Statistical analysis description
    The null hypothesis was that there was no difference between the placebo and the omalizumab 150 mg groups.
    Comparison groups
    Placebo v Omalizumab 150 mg
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 = 0.0017 [16]
    Method
    		 ANCOVA
    Parameter type
    		 Least squares mean difference
    Point estimate
    -3.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.57
         upper limit
    		 -1.32
    Notes
    [15] - Covariates included in the analysis were baseline weekly number of hives score (< median vs ≥ median) and baseline weight (< 80 kg vs ≥ 80 kg).
    [16] - A pre-specified hierarchical order of testing was employed to adjust for the comparison of multiple omalizumab groups to the placebo group in order to maintain an overall type I error rate of 0.05 (2-sided) within each dose.
    Statistical analysis title
    		 Change From Baseline in Hives Score at Week 12
    Statistical analysis description
    The null hypothesis was that there was no difference between the placebo and the omalizumab 300 mg groups.
    Comparison groups
    Placebo v Omalizumab 300 mg
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [17]
    P-value
    		 < 0.0001 [18]
    Method
    		 ANCOVA
    Parameter type
    		 Least squares mean difference
    Point estimate
    -6.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.1
         upper limit
    		 -4.76
    Notes
    [17] - Covariates included in the analysis were baseline weekly number of hives score (< median vs ≥ median) and baseline weight (< 80 kg vs ≥ 80 kg).
    [18] - A pre-specified hierarchical order of testing was employed to adjust for the comparison of multiple omalizumab groups to the placebo group in order to maintain an overall type I error rate of 0.05 (2-sided) within each dose.

    Secondary: Time to Minimally Important Difference (MID) Response in the Weekly Itch Severity Score by Week 12

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    End point title
    		 Time to Minimally Important Difference (MID) Response in the Weekly Itch Severity Score by Week 12
    End point description
    The time to the MID response is the number of weeks from the start of treatment (Baseline) until the time point at which the first MID response occurs. The MID response is defined as a reduction ≥ 5 points from Baseline in the weekly itch severity score. mITT Population: All randomized participants who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo Omalizumab 75 mg Omalizumab 150 mg Omalizumab 300 mg
    Number of subjects analysed
    57
    57
    66
    76
    Units: Weeks
        median (confidence interval 95%)
    4 (2 to 6)
    3 (2 to 5)
    2 (2 to 3)
    1 (1 to 2)
    Statistical analysis title
    		 Time to MID Response in Weekly Itch Severity Score
    Statistical analysis description
    The null hypothesis was that there was no difference between the placebo and the omalizumab 75 mg groups.
    Comparison groups
    Placebo v Omalizumab 75 mg
    Number of subjects included in analysis
    114
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [19]
    P-value
    		 = 0.0879 [20]
    Method
    		 Cox proportional hazards model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.95
         upper limit
    		 2.03
    Notes
    [19] - Covariates included in the analysis were baseline weekly itch severity score (< 13 vs ≥ 13) and baseline weight (< 80 kg vs ≥ 80 kg).
    [20] - A pre-specified hierarchical order of testing was employed to adjust for the comparison of multiple omalizumab groups to the placebo group in order to maintain an overall type I error rate of 0.05 (2-sided) within each dose.
    Statistical analysis title
    		 Time to MID Response in Weekly Itch Severity Score
    Statistical analysis description
    The null hypothesis was that there was no difference between the placebo and the omalizumab 150 mg groups.
    Comparison groups
    Placebo v Omalizumab 150 mg
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [21]
    P-value
    		 = 0.0301 [22]
    Method
    		 Cox proportional hazards model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.04
         upper limit
    		 2.14
    Notes
    [21] - Covariates included in the analysis were baseline weekly itch severity score (< 13 vs ≥ 13) and baseline weight (< 80 kg vs ≥ 80 kg).
    [22] - A pre-specified hierarchical order of testing was employed to adjust for the comparison of multiple omalizumab groups to the placebo group in order to maintain an overall type I error rate of 0.05 (2-sided) within each dose.
    Statistical analysis title
    		 Time to MID Response in Weekly Itch Severity Score
    Statistical analysis description
    The null hypothesis was that there was no difference between the placebo and the omalizumab 300 mg groups.
    Comparison groups
    Placebo v Omalizumab 300 mg
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [23]
    P-value
    		 < 0.0001 [24]
    Method
    		 Cox proportional hazards model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    2.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.63
         upper limit
    		 3.36
    Notes
    [23] - Covariates included in the analysis were baseline weekly itch severity score (< 13 vs ≥ 13) and baseline weight (< 80 kg vs ≥ 80 kg).
    [24] - A pre-specified hierarchical order of testing was employed to adjust for the comparison of multiple omalizumab groups to the placebo group in order to maintain an overall type I error rate of 0.05 (2-sided) within each dose.

    Secondary: Percentage of Participants With a UAS7 Score ≤ 6 at Week 12

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    End point title
    		 Percentage of Participants With a UAS7 Score ≤ 6 at Week 12
    End point description
    The UAS7 is the sum of the daily urticarial activity scores over 7 days and ranges from 0 to 42. The daily urticarial activity score is the average of the morning and evening urticarial activity scores and ranges from 0 to 6. The urticarial activity score is the sum of ratings on a scale of 0 to 3 (0 = none to 3 = intense/severe) for (1) the number of wheals (hives) and (2) itch intensity over the previous 12 hours, ranges from 0 to 6, and is measured twice daily (morning and evening). The Baseline score is the sum of the daily urticarial activity scores over the 7 days prior to the first treatment. A higher urticarial activity score indicates more urticaria activity. mITT Population: All randomized participants who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Placebo Omalizumab 75 mg Omalizumab 150 mg Omalizumab 300 mg
    Number of subjects analysed
    80
    77
    80
    81
    Units: Percentage of participants
        number (not applicable)
    11.3
    26
    40
    51.9
    Statistical analysis title
    		 Percentage of Participants With a UAS7 Score ≤6
    Statistical analysis description
    The null hypothesis was that there was no difference between the placebo and the omalizumab 75 mg groups.
    Comparison groups
    Placebo v Omalizumab 75 mg
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [25]
    P-value
    		 = 0.0148 [26]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [25] - Covariates included in the analysis were baseline UAS7 (< median vs ≥ median) and baseline weight (< 80 kg vs ≥ 80 kg).
    [26] - A pre-specified hierarchical order of testing was employed to adjust for the comparison of multiple omalizumab groups to the placebo group in order to maintain an overall type I error rate of 0.05 (2-sided) within each dose.
    Statistical analysis title
    		 Percentage of Participants With a UAS7 Score ≤6
    Statistical analysis description
    The null hypothesis was that there was no difference between the placebo and the omalizumab 150 mg groups.
    Comparison groups
    Placebo v Omalizumab 150 mg
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [27]
    P-value
    		 < 0.0001 [28]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [27] - Covariates included in the analysis were baseline UAS7 (< median vs ≥ median) and baseline weight (< 80 kg vs ≥ 80 kg).
    [28] - A pre-specified hierarchical order of testing was employed to adjust for the comparison of multiple omalizumab groups to the placebo group in order to maintain an overall type I error rate of 0.05 (2-sided) within each dose.
    Statistical analysis title
    		 Percentage of Participants With a UAS7 Score ≤6
    Statistical analysis description
    The null hypothesis was that there was no difference between the placebo and the omalizumab 300 mg groups.
    Comparison groups
    Placebo v Omalizumab 300 mg
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [29]
    P-value
    		 < 0.0001 [30]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [29] - Covariates included in the analysis were baseline UAS7 (< median vs ≥ median) and baseline weight (< 80 kg vs ≥ 80 kg).
    [30] - A pre-specified hierarchical order of testing was employed to adjust for the comparison of multiple omalizumab groups to the placebo group in order to maintain an overall type I error rate of 0.05 (2-sided) within each dose.

    Secondary: Percentage of Weekly Itch Severity Score MID Responders at Week 12

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    End point title
    		 Percentage of Weekly Itch Severity Score MID Responders at Week 12
    End point description
    The percentage of participants with an itch severity score at 12 Weeks at least 5 points lower than at Baseline. mITT Population: All randomized participants who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo Omalizumab 75 mg Omalizumab 150 mg Omalizumab 300 mg
    Number of subjects analysed
    80
    77
    80
    81
    Units: Percentage of participants
        number (not applicable)
    36.3
    55.8
    56.3
    75.3
    Statistical analysis title
    		 % of Weekly Itch Severity Score MID Responders
    Statistical analysis description
    The null hypothesis was that there was no difference between the placebo and the omalizumab 75 mg groups. The p-value was not evaluated for statistical significance in accordance with the type I error rate control plan.
    Comparison groups
    Placebo v Omalizumab 75 mg
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [31]
    P-value
    		 = 0.0118 [32]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [31] - Covariates included in the analysis were baseline weekly itch severity score (< 13 vs ≥ 13) and baseline weight (< 80 kg vs ≥ 80 kg).
    [32] - A pre-specified hierarchical order of testing was employed to adjust for the comparison of multiple omalizumab groups to the placebo group in order to maintain an overall type I error rate of 0.05 (2-sided) within each dose.
    Statistical analysis title
    		 % of Weekly Itch Severity Score MID Responders
    Statistical analysis description
    The null hypothesis was that there was no difference between the placebo and the omalizumab 150 mg groups.
    Comparison groups
    Placebo v Omalizumab 150 mg
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [33]
    P-value
    		 = 0.0226 [34]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [33] - Covariates included in the analysis were baseline weekly itch severity score (< 13 vs ≥ 13) and baseline weight (< 80 kg vs ≥ 80 kg).
    [34] - A pre-specified hierarchical order of testing was employed to adjust for the comparison of multiple omalizumab groups to the placebo group in order to maintain an overall type I error rate of 0.05 (2-sided) within each dose.
    Statistical analysis title
    		 % of Weekly Itch Severity Score MID Responders
    Statistical analysis description
    The null hypothesis was that there was no difference between the placebo and the omalizumab 300 mg groups.
    Comparison groups
    Placebo v Omalizumab 300 mg
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [35]
    P-value
    		 < 0.0001 [36]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [35] - Covariates included in the analysis were baseline weekly itch severity score (< 13 vs ≥ 13) and baseline weight (< 80 kg vs ≥ 80 kg).
    [36] - A pre-specified hierarchical order of testing was employed to adjust for the comparison of multiple omalizumab groups to the placebo group in order to maintain an overall type I error rate of 0.05 (2-sided) within each dose.

    Secondary: Change From Baseline to Week 12 in the Weekly Size of the Largest Hive Score

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    End point title
    		 Change From Baseline to Week 12 in the Weekly Size of the Largest Hive Score
    End point description
    The weekly size of the largest hive score is the sum of the daily size of the largest hive scores over 7 days and ranges from 0 to 21. The daily size of the largest hive score is assessed twice daily (morning and evening) on a scale of 0 (none) to 3 (> 2.5 cm). The daily size of the largest hive score is the average of the morning and evening scores. The Baseline weekly size of the largest hive score is calculated over the 7 days prior to the first treatment. A higher score indicates larger hives. A negative change score indicates a reduction in hive size. mITT Population: All randomized participants who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo Omalizumab 75 mg Omalizumab 150 mg Omalizumab 300 mg
    Number of subjects analysed
    80
    77
    80
    81
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -3.93 ( 5.44 )
    -6.2 ( 6.29 )
    -6.96 ( 6.68 )
    -9.79 ( 6.66 )
    Statistical analysis title
    		 Change From Baseline in Largest Hive Score
    Statistical analysis description
    The null hypothesis was that there was no difference between the placebo and the omalizumab 75 mg groups. The p-value was not evaluated for statistical significance in accordance with the type I error rate control plan.
    Comparison groups
    Placebo v Omalizumab 75 mg
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [37]
    P-value
    		 = 0.0124 [38]
    Method
    		 ANCOVA
    Parameter type
    		 Least squares mean difference
    Point estimate
    -2.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.17
         upper limit
    		 -0.51
    Notes
    [37] - Covariates included in the analysis were baseline weekly size of largest hive score (< median vs ≥ median) and baseline weight (<80 kg vs ≥80 kg).
    [38] - A pre-specified hierarchical order of testing was employed to adjust for the comparison of multiple omalizumab groups to the placebo group in order to maintain an overall type I error rate of 0.05 (2-sided) within each dose.
    Statistical analysis title
    		 Change From Baseline in Largest Hive Score
    Statistical analysis description
    The null hypothesis was that there was no difference between the placebo and the omalizumab 150 mg groups.
    Comparison groups
    Placebo v Omalizumab 150 mg
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [39]
    P-value
    		 = 0.0012 [40]
    Method
    		 ANCOVA
    Parameter type
    		 Least squares mean difference
    Point estimate
    -3.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.05
         upper limit
    		 -1.27
    Notes
    [39] - Covariates included in the analysis were baseline weekly size of largest hive score (< median vs ≥ median) and baseline weight (<80 kg vs ≥80 kg).
    [40] - A pre-specified hierarchical order of testing was employed to adjust for the comparison of multiple omalizumab groups to the placebo group in order to maintain an overall type I error rate of 0.05 (2-sided) within each dose.
    Statistical analysis title
    		 Change From Baseline in Largest Hive Score
    Statistical analysis description
    The null hypothesis was that there was no difference between the placebo and the omalizumab 300 mg groups.
    Comparison groups
    Placebo v Omalizumab 300 mg
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [41]
    P-value
    		 < 0.0001 [42]
    Method
    		 ANCOVA
    Parameter type
    		 Least squares mean difference
    Point estimate
    -5.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.59
         upper limit
    		 -3.87
    Notes
    [41] - Covariates included in the analysis were baseline weekly size of largest hive score (< median vs ≥ median) and baseline weight (<80 kg vs ≥80 kg).
    [42] - A pre-specified hierarchical order of testing was employed to adjust for the comparison of multiple omalizumab groups to the placebo group in order to maintain an overall type I error rate of 0.05 (2-sided) within each dose.

    Secondary: Change From Baseline in the Overall Dermatology Life Quality Index (DLQI) Score at Week 12

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    End point title
    		 Change From Baseline in the Overall Dermatology Life Quality Index (DLQI) Score at Week 12
    End point description
    The DLQI is a 10-item dermatology-specific health-related quality of life measure. Participants rated their dermatology symptoms as well as the impact of their skin condition on various aspects of their lives on a scale of 0 (Not at all) to 3 (Very much). The overall DLQI is the sum of the responses to the 10 items and ranges from 0 to 30. A lower score indicates a better quality of life. A negative change score indicates improvement.mITT Population: All randomized participants who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo Omalizumab 75 mg Omalizumab 150 mg Omalizumab 300 mg
    Number of subjects analysed
    62 [43]
    66 [44]
    63 [45]
    72 [46]
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -6.13 ( 6.25 )
    -6.33 ( 6.08 )
    -8 ( 7.24 )
    -10.29 ( 7.23 )
    Notes
    [43] - n (number) = participants with values at both Baseline and Week 12 were included in the analysis.
    [44] - n (number) = participants with values at both Baseline and Week 12 were included in the analysis.
    [45] - n (number) = participants with values at both Baseline and Week 12 were included in the analysis.
    [46] - n (number) = participants with values at both Baseline and Week 12 were included in the analysis.
    Statistical analysis title
    		 Change From Baseline in the Overall DLQI Score
    Statistical analysis description
    The null hypothesis was that there was no difference between the placebo and the omalizumab 75 mg groups. The p-value was not evaluated for statistical significance in accordance with the type I error rate control plan.
    Comparison groups
    Placebo v Omalizumab 75 mg
    Number of subjects included in analysis
    128
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [47]
    P-value
    		 = 0.7956 [48]
    Method
    		 ANCOVA
    Parameter type
    		 Least squares mean difference
    Point estimate
    0.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.76
         upper limit
    		 2.28
    Notes
    [47] - Covariates included in the analysis were baseline overall DLQI score (< median vs ≥ median) and baseline weight (<80 kg vs ≥80 kg).
    [48] - A pre-specified hierarchical order of testing was employed to adjust for the comparison of multiple omalizumab groups to the placebo group in order to maintain an overall type I error rate of 0.05 (2-sided) within each dose.
    Statistical analysis title
    		 Change From Baseline in the Overall DLQI Score
    Statistical analysis description
    The null hypothesis was that there was no difference between the placebo and the omalizumab 150 mg groups.
    Comparison groups
    Placebo v Omalizumab 150 mg
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [49]
    P-value
    		 = 0.2286 [50]
    Method
    		 ANCOVA
    Parameter type
    		 Least squares mean difference
    Point estimate
    -1.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.46
         upper limit
    		 0.84
    Notes
    [49] - Covariates included in the analysis were baseline overall DLQI score (< median vs ≥ median) and baseline weight (<80 kg vs ≥80 kg).
    [50] - A pre-specified hierarchical order of testing was employed to adjust for the comparison of multiple omalizumab groups to the placebo group in order to maintain an overall type I error rate of 0.05 (2-sided) within each dose.
    Statistical analysis title
    		 Change From Baseline in the Overall DLQI Score
    Statistical analysis description
    The null hypothesis was that there was no difference between the placebo and the omalizumab 300 mg groups.
    Comparison groups
    Placebo v Omalizumab 300 mg
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [51]
    P-value
    		 < 0.0001 [52]
    Method
    		 ANCOVA
    Parameter type
    		 Least squares mean difference
    Point estimate
    -4.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.96
         upper limit
    		 -2.2
    Notes
    [51] - Covariates included in the analysis were baseline overall DLQI score (< median vs ≥ median) and baseline weight (<80 kg vs ≥80 kg).
    [52] - A pre-specified hierarchical order of testing was employed to adjust for the comparison of multiple omalizumab groups to the placebo group in order to maintain an overall type I error rate of 0.05 (2-sided) within each dose.

    Secondary: Percentage of Angioedema-free Days From Week 4 to Week 12

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    End point title
    		 Percentage of Angioedema-free Days From Week 4 to Week 12
    End point description
    The percentage of angioedema-free days from Weeks 4 to 12 was defined as the number of days for which a participant responded “No” to the angioedema question in the daily diary divided by the total number of days with a non-missing diary entry, starting at the Week 4 visit and ending the day prior to the Week 12 visit. mITT Population: All randomized participants who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Week 4 to Week 12
    End point values
    		 Placebo Omalizumab 75 mg Omalizumab 150 mg Omalizumab 300 mg
    Number of subjects analysed
    66 [53]
    69 [54]
    70 [55]
    74 [56]
    Units: Percentage
        arithmetic mean (standard deviation)
    88.2 ( 19.4 )
    86.5 ( 28.4 )
    89.6 ( 20.6 )
    96.1 ( 11.3 )
    Notes
    [53] - n (number) = participants with nonmissing values at Week 4 and Week 12 were included in the analysis
    [54] - n (number) = participants with nonmissing values at Week 4 and Week 12 were included in the analysis
    [55] - n (number) = participants with nonmissing values at Week 4 and Week 12 were included in the analysis
    [56] - n (number) = participants with nonmissing values at Week 4 and Week 12 were included in the analysis
    Statistical analysis title
    		 % of Angioedema-free Days From Week 4 to Week 12
    Statistical analysis description
    The null hypothesis was that there was no difference between the placebo and the omalizumab 75 mg groups. The p-value was not evaluated for statistical significance in accordance with the type I error rate control plan.
    Comparison groups
    Placebo v Omalizumab 75 mg
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [57]
    P-value
    		 = 0.4867 [58]
    Method
    		 Stratified Wilcoxon
    Confidence interval
    Notes
    [57] - Stratification variables included in the analysis were presence of angioedema at baseline (yes vs no) and baseline weight (< 80 kg vs ≥ 80 kg).
    [58] - A pre-specified hierarchical order of testing was employed to adjust for the comparison of multiple omalizumab groups to the placebo group in order to maintain an overall type I error rate of 0.05 (2-sided) within each dose.
    Statistical analysis title
    		 % of Angioedema-free Days From Week 4 to Week 12
    Statistical analysis description
    The null hypothesis was that there was no difference between the placebo and the omalizumab 150 mg groups. The p-value was not evaluated for statistical significance in accordance with the type I error rate control plan.
    Comparison groups
    Placebo v Omalizumab 150 mg
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [59]
    P-value
    		 = 0.1747 [60]
    Method
    		 Stratified Wilcoxon
    Confidence interval
    Notes
    [59] - Stratification variables included in the analysis were presence of angioedema at baseline (yes vs no) and baseline weight (< 80 kg vs ≥ 80 kg).
    [60] - A pre-specified hierarchical order of testing was employed to adjust for the comparison of multiple omalizumab groups to the placebo group in order to maintain an overall type I error rate of 0.05 (2-sided) within each dose.
    Statistical analysis title
    		 % of Angioedema-free Days From Week 4 to Week 12
    Statistical analysis description
    The null hypothesis was that there was no difference between the placebo and the omalizumab 300 mg groups. The p-value was not evaluated for statistical significance in accordance with the type I error rate control plan.
    Comparison groups
    Placebo v Omalizumab 300 mg
    Number of subjects included in analysis
    140
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [61]
    P-value
    		 < 0.0001 [62]
    Method
    		 Stratified Wilcoxon
    Confidence interval
    Notes
    [61] - Stratification variables included in the analysis were presence of angioedema at baseline (yes vs no) and baseline weight (< 80 kg vs ≥ 80 kg).
    [62] - A pre-specified hierarchical order of testing was employed to adjust for the comparison of multiple omalizumab groups to the placebo group in order to maintain an overall type I error rate of 0.05 (2-sided) within each dose.

    Secondary: Percentage of Complete Responders (UAS7 = 0) at Week 12

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    End point title
    		 Percentage of Complete Responders (UAS7 = 0) at Week 12
    End point description
    A complete responder was defined as a participant with a UAS7 score = 0 at Week 12. mITT Population: All randomized participants who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Placebo Omalizumab 75 mg Omalizumab 150 mg Omalizumab 300 mg
    Number of subjects analysed
    80
    77
    80
    81
    Units: Percentage of participants
        number (not applicable)
    8.8
    11.7
    15
    35.8
    Statistical analysis title
    		 % of Complete Responders (UAS7 = 0) at Week 12
    Statistical analysis description
    The null hypothesis was that there was no difference between the placebo and the omalizumab 75 mg groups. The p-value was not evaluated for statistical significance in accordance with the type I error rate control plan.
    Comparison groups
    Placebo v Omalizumab 75 mg
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [63]
    P-value
    		 = 0.458 [64]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [63] - Covariates included in the analysis were baseline UAS7 (< median vs ≥ median) and baseline weight (<80 kg vs ≥80 kg).
    [64] - A pre-specified hierarchical order of testing was employed to adjust for the comparison of multiple omalizumab groups to the placebo group in order to maintain an overall type I error rate of 0.05 (2-sided) within each dose.
    Statistical analysis title
    		 % of Complete Responders (UAS7 = 0) at Week 12
    Statistical analysis description
    The null hypothesis was that there was no difference between the placebo and the omalizumab 150 mg groups. The p-value was not evaluated for statistical significance in accordance with the type I error rate control plan.
    Comparison groups
    Placebo v Omalizumab 150 mg
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [65]
    P-value
    		 = 0.2087 [66]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [65] - Covariates included in the analysis were baseline UAS7 (< median vs ≥ median) and baseline weight (<80 kg vs ≥80 kg).
    [66] - A pre-specified hierarchical order of testing was employed to adjust for the comparison of multiple omalizumab groups to the placebo group in order to maintain an overall type I error rate of 0.05 (2-sided) within each dose.
    Statistical analysis title
    		 % of Complete Responders (UAS7 = 0) at Week 12
    Statistical analysis description
    The null hypothesis was that there was no difference between the placebo and the omalizumab 300 mg groups. The p-value was not evaluated for statistical significance in accordance with the type I error rate control plan.
    Comparison groups
    Placebo v Omalizumab 300 mg
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [67]
    P-value
    		 < 0.0001 [68]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [67] - Covariates included in the analysis were baseline UAS7 (< median vs ≥ median) and baseline weight (<80 kg vs ≥80 kg).
    [68] - A pre-specified hierarchical order of testing was employed to adjust for the comparison of multiple omalizumab groups to the placebo group in order to maintain an overall type I error rate of 0.05 (2-sided) within each dose.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported starting with the first dose of study drug through the end of the study (up to 40 weeks).
    Adverse event reporting additional description
    Safety population: All randomized participants who received at least 1 dose of study drug.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo subcutaneously every 4 weeks during the 24 week treatment period.

    Reporting group title
    Omalizumab 75 mg
    Reporting group description
    		 Participants received omalizumab 75 mg subcutaneously every 4 weeks during the 24 week treatment period.

    Reporting group title
    Omalizumab 150 mg
    Reporting group description
    		 Participants received omalizumab 150 mg subcutaneously every 4 weeks during the 24 week treatment period.

    Reporting group title
    Omalizumab 300 mg
    Reporting group description
    		 Participants received omalizumab 300 mg subcutaneously every 4 weeks during the 24 week treatment period.

    Serious adverse events
    		 Placebo Omalizumab 75 mg Omalizumab 150 mg Omalizumab 300 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 80 (6.25%)
    2 / 70 (2.86%)
    5 / 87 (5.75%)
    2 / 81 (2.47%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Radius fracture
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 70 (0.00%)
    0 / 87 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 70 (0.00%)
    1 / 87 (1.15%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 70 (0.00%)
    1 / 87 (1.15%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Abortion induced
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 70 (0.00%)
    1 / 87 (1.15%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 70 (0.00%)
    0 / 87 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 70 (1.43%)
    0 / 87 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Cervical dysplasia
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 70 (0.00%)
    0 / 87 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 70 (0.00%)
    0 / 87 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 70 (1.43%)
    1 / 87 (1.15%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angioedema
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 70 (0.00%)
    1 / 87 (1.15%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Idiopathic urticaria
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 70 (0.00%)
    0 / 87 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 70 (0.00%)
    1 / 87 (1.15%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 70 (0.00%)
    1 / 87 (1.15%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Shock hypoglycaemic
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 70 (0.00%)
    0 / 87 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 70 (0.00%)
    0 / 87 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Omalizumab 75 mg Omalizumab 150 mg Omalizumab 300 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    36 / 80 (45.00%)
    37 / 70 (52.86%)
    45 / 87 (51.72%)
    40 / 81 (49.38%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 80 (3.75%)
    5 / 70 (7.14%)
    12 / 87 (13.79%)
    7 / 81 (8.64%)
         occurrences all number
    3
    5
    12
    9
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    4 / 80 (5.00%)
    1 / 70 (1.43%)
    4 / 87 (4.60%)
    2 / 81 (2.47%)
         occurrences all number
    7
    1
    5
    2
    Oropharyngeal pain
         subjects affected / exposed
    4 / 80 (5.00%)
    2 / 70 (2.86%)
    5 / 87 (5.75%)
    0 / 81 (0.00%)
         occurrences all number
    4
    2
    6
    0
    Cough
         subjects affected / exposed
    3 / 80 (3.75%)
    4 / 70 (5.71%)
    3 / 87 (3.45%)
    0 / 81 (0.00%)
         occurrences all number
    3
    4
    3
    0
    Skin and subcutaneous tissue disorders
    Idiopathic urticaria
         subjects affected / exposed
    4 / 80 (5.00%)
    10 / 70 (14.29%)
    6 / 87 (6.90%)
    11 / 81 (13.58%)
         occurrences all number
    4
    13
    8
    13
    Urticaria
         subjects affected / exposed
    8 / 80 (10.00%)
    8 / 70 (11.43%)
    7 / 87 (8.05%)
    5 / 81 (6.17%)
         occurrences all number
    15
    9
    7
    6
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 80 (0.00%)
    3 / 70 (4.29%)
    5 / 87 (5.75%)
    4 / 81 (4.94%)
         occurrences all number
    0
    4
    9
    5
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    16 / 80 (20.00%)
    5 / 70 (7.14%)
    14 / 87 (16.09%)
    10 / 81 (12.35%)
         occurrences all number
    17
    5
    16
    12
    Sinusitis
         subjects affected / exposed
    5 / 80 (6.25%)
    6 / 70 (8.57%)
    7 / 87 (8.05%)
    5 / 81 (6.17%)
         occurrences all number
    5
    6
    10
    7
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 80 (3.75%)
    6 / 70 (8.57%)
    4 / 87 (4.60%)
    4 / 81 (4.94%)
         occurrences all number
    3
    8
    7
    4
    Bronchitis
         subjects affected / exposed
    6 / 80 (7.50%)
    5 / 70 (7.14%)
    2 / 87 (2.30%)
    2 / 81 (2.47%)
         occurrences all number
    6
    5
    2
    2
    Urinary tract infection
         subjects affected / exposed
    3 / 80 (3.75%)
    3 / 70 (4.29%)
    7 / 87 (8.05%)
    2 / 81 (2.47%)
         occurrences all number
    3
    3
    7
    2

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Jan 2011
    • The number of weeks that a participant must have had chronic idiopathic urticaria (CIU) symptoms despite being on H1 antihistamines was increased from 6 to 8 weeks. • The secondary objectives were clarified to indicate that a goal of this study was to provide information regarding the recurrence of disease/symptoms after withdrawal of omalizumab in participants with refractory CIU. Secondary and exploratory endpoints were modified as a result. • Procedures regarding the use of excluded therapy were modified in an effort to continue to follow participants for safety evaluation after they had discontinued study drug treatment. • The washout period required after regular doxepin use prior to enrollment was reduced from 6 weeks to 14 days. • The criterion for women of childbearing potential and pregnancy was clarified. Additionally, nursing women were excluded from study participation. • Contraindications to diphenydramine were added. • The in-clinic urticaria activity score terminology was corrected. • The start of the screening period was modified from 14−18 to 12−18 days prior to Day 1. • The difference between discontinuation from study treatment and discontinuation from the study was clarified. • The Medical Monitor was replaced.

    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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