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    Clinical Trial Results:
    A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled Safety Study of Xolair (Omalizumab) in Patients With Chronic Idiopathic Urticaria (CIU) who Remain Symptomatic Despite Treatment With H1 Antihistamines, H2 Blockers, and/or Leukotriene Receptor Antagonists

    Summary
    EudraCT number
    		 2010-022784-35
    Trial protocol
    		 GB   DE  
    Global end of trial date
    22 Nov 2012

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Jul 2016
    First version publication date
    09 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GA00889 (Q4883)
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01264939
    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
    22 Nov 2012
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Nov 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 safety and efficacy of omalizumab administered subcutaneously as add on therapy for the treatment of adolescent and adult participants (12-75 years of age) diagnosed with CIU receiving concomitant therapy including H1 antihistamines at increased doses (up to four times the approved dose), H2 blockers, and/or leukotriene receptor antagonist (LTRAs).
    Protection of trial subjects
    This study was conducted in accordance with the United States 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
    21 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
    Poland: 10
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    Germany: 29
    Country: Number of subjects enrolled
    United States: 270
    Country: Number of subjects enrolled
    Australia: 13
    Country: Number of subjects enrolled
    New Zealand: 4
    Country: Number of subjects enrolled
    Singapore: 2
    Worldwide total number of subjects
    336
    EEA total number of subjects
    47
    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)
    11
    Adults (18-64 years)
    303
    From 65 to 84 years
    22
    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. One participant in the placebo group was withdrawn after randomization but before receiving treatment due to an adverse event. This participant is 1 of 18 in this reporting group who did not complete the study.

    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

    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 subcutaneous (SC) injection every 4 weeks during the 24-week double-blind treatment period.

    Arm title
    		 Omalizumab
    Arm description
    		 Participants received omalizumab 300 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 300 mg of omalizumab administered by SC injection every 4 weeks during the 24-week double-blind treatment period.

    Number of subjects in period 1
    		Placebo Omalizumab
    Started
    84
    252
    Completed
    66
    224
    Not completed
    18
    28
         Physician decision
    1
    1
         Participant/Guardian decision
    8
    10
         Disease progression
    8
    11
         Adverse event, non-fatal
    1
    3
         Lost to follow-up
    -
    3

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

    Reporting group values
    		 Placebo Omalizumab Total
    Number of subjects
    		 84 252 336
    Age categorical
    Units: Subjects
    Age continuous
    Modified intent-to-treat (mITT) Population: All randomized participants who received at least 1 dose of study drug. One participant (randomized to placebo) did not receive study drug and was not included in the mITT population.
    Units: years
        arithmetic mean (standard deviation)
    		 44.6 ± 14.9 42.7 ± 13.9 -
    Gender categorical
    Units: Subjects
        Female
    		 56 186 242
        Male
    		 28 66 94

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

    Primary: Percentage of Participants With Adverse Events

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    End point title
    		 Percentage of Participants With Adverse Events [1]
    End point description
    The percentage of participants with serious adverse events and other adverse events is summarized by Medical Dictionary for Regulatory Activities (MedDRA) preferred terms and organ classes in the Reported Adverse Events section below. Safety population: All randomized participants who received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Baseline to the end of study (up to 40 weeks)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was performed because only descriptive statistics were planned as per protocol.
    End point values
    		 Placebo Omalizumab
    Number of subjects analysed
    83
    252
    Units: Percentage of participants
        number (not applicable)
    78.3
    83.7
    No statistical analyses for this end point

    Secondary: 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. One participant (randomized to placebo) did not receive study drug and was not included in the mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo Omalizumab
    Number of subjects analysed
    83
    252
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -4.01 ± 5.87
    -8.55 ± 6.01
    Statistical analysis title
    		 Change From Baseline 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
    Number of subjects included in analysis
    335
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 < 0.0001 [3]
    Method
    		 ANCOVA
    Parameter type
    		 Least squares mean difference
    Point estimate
    -4.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.97
         upper limit
    		 -3.08
    Notes
    [2] - Covariates included in the analysis were baseline weekly itch severity score (less than [<] 13 versus [vs] greater than or equal to [≥] 13) and baseline weight (< 80 kilogram [kg] vs ≥80 kg).
    [3] - Multiplicity plan applied to the efficacy endpoints provided strong control of the type I error rate at 0.05 level by pre-specifying the hierarchical order of the efficacy endpoint tests.

    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
    Number of subjects analysed
    83
    252
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -8.5 ± 11.71
    -19.01 ± 13.15
    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
    Number of subjects included in analysis
    335
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 < 0.0001 [5]
    Method
    		 ANCOVA
    Parameter type
    		 Least squares mean difference
    Point estimate
    -10.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.17
         upper limit
    		 -6.86
    Notes
    [4] - Covariates included in the analysis were baseline UAS7 (< median vs ≥ median) and baseline weight (<80 kg vs ≥80 kg).
    [5] - Multiplicity plan applied to the efficacy endpoints provided strong control of the type I error rate at 0.05 level by pre-specifying the hierarchical order of the efficacy endpoint tests.

    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 (greater than [>] 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
    Number of subjects analysed
    83
    252
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -4.49 ± 6.33
    -10.46 ± 7.74
    Statistical analysis title
    		 Change From Baseline in Weekly Hives 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
    Number of subjects included in analysis
    335
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 < 0.0001 [7]
    Method
    		 ANCOVA
    Parameter type
    		 Least squares mean difference
    Point estimate
    -5.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.72
         upper limit
    		 -4.07
    Notes
    [6] - Covariates included in the analysis were baseline weekly number of hives score (< median vs ≥ median) and baseline weight (<80 kg vs ≥80 kg).
    [7] - Multiplicity plan applied to the efficacy endpoints provided strong control of the type I error rate at 0.05 level by pre-specifying the hierarchical order of the efficacy endpoint tests.

    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. 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. mITT Population: All randomized participants who received at least 1 dose of study drug. Only participants with a MID response were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo Omalizumab
    Number of subjects analysed
    83
    252
    Units: Weeks
        median (confidence interval 95%)
    5 (3 to 7)
    2 (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 300 mg groups.
    Comparison groups
    Placebo v Omalizumab
    Number of subjects included in analysis
    335
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 < 0.0001 [9]
    Method
    		 Cox proportional hazards model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.47
         upper limit
    		 2.68
    Notes
    [8] - Covariates included in the analysis were baseline weekly itch severity score (< 13 vs ≥ 13) and baseline weight (<80 kg vs ≥80 kg).
    [9] - Multiplicity plan applied to the efficacy endpoints provided strong control of the type I error rate at 0.05 level by pre-specifying the hierarchical order of the efficacy endpoint tests.

    Secondary: Percentage of Participants With a UAS7 Score Less Than or Equal to (≤) 6 at Week 12

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    End point title
    		 Percentage of Participants With a UAS7 Score Less Than or Equal to (≤) 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
    Number of subjects analysed
    83
    252
    Units: Percentage of participants
        number (not applicable)
    12
    52.4
    Statistical analysis title
    		 % of Participants With a UAS7 Score ≤6 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
    Number of subjects included in analysis
    335
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 < 0.0001 [11]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [10] - Covariates included in the analysis were baseline UAS7 (< median vs ≥ median) and baseline weight (<80 kg vs ≥80 kg).
    [11] - Multiplicity plan applied to the efficacy endpoints provided strong control of the type I error rate at 0.05 level by pre-specifying the hierarchical order of the efficacy endpoint tests.

    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. 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. Modified intent-to-treat 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
    Number of subjects analysed
    83
    252
    Units: Percentage of participants
        number (not applicable)
    39.8
    69.8
    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
    Number of subjects included in analysis
    335
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [12]
    P-value
    		 < 0.0001 [13]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [12] - Covariates included in the analysis were baseline weekly itch severity score (< 13 vs ≥ 13) and baseline weight (<80 kg vs ≥80 kg).
    [13] - Multiplicity plan applied to the efficacy endpoints provided strong control of the type I error rate at 0.05 level by pre-specifying the hierarchical order of the efficacy endpoint tests.

    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
    Number of subjects analysed
    83
    252
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -3.09 ± 5.46
    -8.82 ± 7.23
    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
    Number of subjects included in analysis
    335
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [14]
    P-value
    		 < 0.0001 [15]
    Method
    		 ANCOVA
    Parameter type
    		 Least squares mean difference
    Point estimate
    -5.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.25
         upper limit
    		 -3.96
    Notes
    [14] - Covariates included in the analysis were baseline weekly size of largest hive score (< median vs ≥ median) and baseline weight (< 80 kg vs ≥ 80 kg).
    [15] - Multiplicity plan applied to the efficacy endpoints provided strong control of the type I error rate at 0.05 level by pre-specifying the hierarchical order of the efficacy endpoint tests.

    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 and who had a DLQI score at Week 12.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo Omalizumab
    Number of subjects analysed
    64
    216
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -5.11 ± 7.53
    -9.69 ± 6.85
    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
    Number of subjects included in analysis
    280
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [16]
    P-value
    		 < 0.0001 [17]
    Method
    		 ANCOVA
    Parameter type
    		 Least squares mean difference
    Point estimate
    -4.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.28
         upper limit
    		 -3.06
    Notes
    [16] - Covariates included in the analysis were baseline overall DLQI score (< median vs ≥ median) and baseline weight (<80 kg vs ≥80 kg).
    [17] - Multiplicity plan applied to the efficacy endpoints provided strong control of the type I error rate at 0.05 level by pre-specifying the hierarchical order of the efficacy endpoint tests.

    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. Participants who withdrew before the Week 4 visit or who had missing responses for more than 40% of the daily diary entries between the Week 4 visit and the Week 12 visit were not included in the analysis.
    End point type
    Secondary
    End point timeframe
    Week 4 to Week 12
    End point values
    		 Placebo Omalizumab
    Number of subjects analysed
    68
    224
    Units: Percentage of days
        arithmetic mean (standard deviation)
    88.1 ± 18.9
    91 ± 21
    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.
    Comparison groups
    Placebo v Omalizumab
    Number of subjects included in analysis
    292
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [18]
    P-value
    		 = 0.0006 [19]
    Method
    		 Stratified Wilcoxon
    Confidence interval
    Notes
    [18] - Stratification variables included in the analysis were presence of angioedema at baseline (yes vs no) and baseline weight (<80 kg vs ≥80 kg).
    [19] - Multiplicity plan applied to the efficacy endpoints provided strong control of the type I error rate at 0.05 level by pre-specifying the hierarchical order of the efficacy endpoint tests.

    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. 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
    Number of subjects analysed
    83
    252
    Units: Percentage of participants
        number (not applicable)
    4.8
    33.7
    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.
    Comparison groups
    Placebo v Omalizumab
    Number of subjects included in analysis
    335
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [20]
    P-value
    		 < 0.0001 [21]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [20] - Covariates included in the analysis were baseline UAS7 (< median vs ≥ median) and baseline weight (<80 kg vs ≥80 kg).
    [21] - Multiplicity plan applied to the efficacy endpoints provided strong control of the type I error rate at 0.05 level by pre-specifying the hierarchical order of the efficacy endpoint tests.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported that started on or after the first treatment date 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. Multiple occurrences of a specific adverse event for a patient were counted once in the frequency for the adverse event.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Omalizumab
    Reporting group description
    		 Participants received omalizumab 300 mg subcutaneously every 4 weeks during the 24-week double-blind treatment period .

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo subcutaneously every 4 weeks during the 24 week treatment period.

    Serious adverse events
    		 Omalizumab Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    18 / 252 (7.14%)
    5 / 83 (6.02%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Intermittent claudication
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory distre
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood glucose increased
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood pressure increased
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Multiple drug overdose
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastric ulcer
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    4 / 252 (1.59%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    2 / 252 (0.79%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Idiopathic urticaria
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Viral infection
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic abscess
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retroperitoneal infection
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 83 (1.20%)
         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
    139 / 252 (55.16%)
    39 / 83 (46.99%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    26 / 252 (10.32%)
    6 / 83 (7.23%)
         occurrences all number
    44
    18
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    15 / 252 (5.95%)
    5 / 83 (6.02%)
         occurrences all number
    15
    7
    Diarrhoea
         subjects affected / exposed
    13 / 252 (5.16%)
    5 / 83 (6.02%)
         occurrences all number
    13
    5
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    11 / 252 (4.37%)
    7 / 83 (8.43%)
         occurrences all number
    11
    7
    Sinus congestion
         subjects affected / exposed
    3 / 252 (1.19%)
    5 / 83 (6.02%)
         occurrences all number
    3
    7
    Skin and subcutaneous tissue disorders
    Idiopathic urticaria
         subjects affected / exposed
    37 / 252 (14.68%)
    10 / 83 (12.05%)
         occurrences all number
    54
    14
    Urticaria
         subjects affected / exposed
    14 / 252 (5.56%)
    3 / 83 (3.61%)
         occurrences all number
    19
    3
    Infections and infestations
    Sinusitis
         subjects affected / exposed
    31 / 252 (12.30%)
    7 / 83 (8.43%)
         occurrences all number
    43
    9
    Nasopharyngitis
         subjects affected / exposed
    27 / 252 (10.71%)
    8 / 83 (9.64%)
         occurrences all number
    34
    11
    Upper respiratory tract infection
         subjects affected / exposed
    27 / 252 (10.71%)
    4 / 83 (4.82%)
         occurrences all number
    34
    5
    Urinary tract infection
         subjects affected / exposed
    14 / 252 (5.56%)
    1 / 83 (1.20%)
         occurrences all number
    16
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Jan 2011
    There were two region-specific changes in protocol which are summarized below: North America/Asia-Pacific protocol (Version 1.0): • The study entry criterion regarding women of childbearing potential was modified, i.e., women of child-bearing potential were excluded from enrollment in the study. • Nursing women were excluded from enrollment into the study. • The prescribed washout period after regular doxepin use prior to enrollment was reduced from 6 weeks to 14 days. European Union protocol (Version 1.1): • Nursing women were excluded from enrollment into the study. • The prescribed washout period after regular doxepin use prior to enrollment was reduced from 6 weeks to 14 days. • Additional minor changes were made for clarity and consistency.

    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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