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    Clinical Trial Results:
    A PHASE III, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, DOSE-RANGING, PLACEBO-CONTROLLED STUDY TO EVALUATE THE EFFICACY, RESPONSE DURATION AND SAFETY OF XOLAIR (OMALIZUMAB) IN PATIENTS WITH CHRONIC IDIOPATHIC URTICARIA (CIU) WHO REMAIN SYMPTOMATIC DESPITE ANTIHISTAMINE TREATMENT (H1)

    Summary
    EudraCT number
    		 2010-022785-27
    Trial protocol
    		 FR   DE   DK   IT   ES  
    Global end of trial date
    27 Jun 2012

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Apr 2016
    First version publication date
    08 Apr 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    Q4882g
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01292473
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Genentech, Inc.
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, 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
    29 Aug 2012
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Jun 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Jun 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of omalizumab compared with placebo in participants with refractory chronic idiopathic urticaria (CIU) receiving concomitant H1 antihistamine therapy
    Protection of trial subjects
    This study was conducted in accordance with the United States (U.S.) Food and Drug Administration (FDA) regulations, 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. For example, the U.S. sites, investigators were trained in GCP according to Genentech and Quintiles standard operating procedures and a written commitment from investigators to comply with GCP was obtained. Approval from the independent ethics committee/institutional review board was obtained before study start-up and prior to implementation of any protocol amendments. The approval from the relevant competent authority prior to starting the study was also obtained. An Independent data monitoring committee was established to monitor safety and study conduct; the members of whom were external to the Sponsor and met at regular intervals (at least once every 6 months) until the end of the trial. A separate anaphylaxis review committee comprised of external experts in CIU and anaphylaxis was convened to clinically review anaphylaxis cases in a blinded fashion.
    Background therapy
    		 All participants received standard-of-care H1 antihistamine treatment at approved doses during the screening, treatment, and follow-up periods. Diphenhydramine (25 mg) treatment was provided on an as-needed basis (up to a maximum of three doses in 24 hours, based on local regulations) during the screening, treatment, and follow-up periods. The medications approved for use in the countries outside the U. S. where the study was conducted were cetirizine 5 or 10 mg once per day (QD), levocetirizine dihydrochloride 2.5 or 5 mg QD, fexofenadine 60 mg twice per day or 180 mg QD, loratadine 10 mg QD, and desloratadine 5 mg QD. Medications for diseases other than CIU (asthma or gastroesophageal reflux disease) were permitted during the study.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Mar 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 6 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 234
    Country: Number of subjects enrolled
    Turkey: 5
    Country: Number of subjects enrolled
    Poland: 18
    Country: Number of subjects enrolled
    Spain: 10
    Country: Number of subjects enrolled
    Denmark: 4
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Germany: 44
    Country: Number of subjects enrolled
    Italy: 4
    Worldwide total number of subjects
    322
    EEA total number of subjects
    83
    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)
    10
    Adults (18-64 years)
    294
    From 65 to 84 years
    18
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted in six European countries along with Turkey and the U.S. from 11 Mar 2011 to 27 Jun 2012. A total of 466 participants were enrolled.

    Pre-assignment
    Screening details
    		 Out of 466 participants, 322 were randomized (79 in the Placebo group, 82 in the Omalizumab 75 mg group, 82 in the Omalizumab 150 mg group, and 79 in the Omalizumab 300 mg group). The most frequent reasons for screen failures were evidence of current drug or alcohol abuse, contraindications to diphenhydramine, and other.

    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, Carer, Assessor
    Blinding implementation details
    Study drug supplies were shipped blinded to each site. An individual not involved with evaluating the participant was identified to administer the study drug. There were no treatment assignment unblindings during the study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants received only placebo injections (i.e., no active treatment)
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received the placebo subcutaneously every 4 weeks on Day 1, Week 4, and Week 8 upon reconstitution with 1.4 mL sterile water for injection (SWFI). Doses of more than 150 mg were divided among multiple injection sites to limit injections to not more than 150 mg per site. Each placebo vial contained 145.5 mg sucrose, 2.8 mg L-histidine hydrochloride monohydrate, 1.8 mg L-histidine, and 0.5 mg polysorbate 20. Each vial was designed to deliver 150 mg of omalizumab in 1.2 mL after reconstitution with 1.4 mL SWFI, USP.

    Arm title
    		 Omalizumab 75 mg
    Arm description
    		 Participants received at least one 75 mg omalizumab injection but no higher active dose level (150 mg or 300 mg) injections during the treatment period. Six participants were randomized to the Omalizumab 75 mg group received at least one dose of omalizumab 150 mg during the treatment period and were therefore included in the Omalizumab 150 mg group.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Omalizumab
    Investigational medicinal product code
    RO5489789
    Other name
    Xolair
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received 75 mg omalizumab subcutaneously on Day 1, Week 4, and Week 8, reconstituted with 1.4 mL SWFI. Each omalizumab vial contained 202.5 mg omalizumab, 145.5 mg sucrose, 2.8 mg, L-histidine hydrochloride monohydrate, 1.8 mg L-histidine, and 0.5 mg polysorbate 20. Each vial was designed to deliver 150 mg of omalizumab in 1.2 mL after reconstitution with 1.4 mL SWFI, USP.

    Arm title
    		 Omalizumab 150 mg
    Arm description
    		 Participants who received at least one 150 mg omalizumab injection but no higher active dose level (300 mg) injections during the treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Omalizumab
    Investigational medicinal product code
    RO5489789
    Other name
    Xolair
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received 150 mg omalizumab subcutaneously on Day 1, Week 4, and Week 8, reconstituted with 1.4 mL SWFI. Each omalizumab vial contained 202.5 mg omalizumab, 145.5 mg sucrose, 2.8 mg, L-histidine hydrochloride monohydrate, 1.8 mg L-histidine, and 0.5 mg polysorbate 20. Each vial was designed to deliver 150 mg of omalizumab in 1.2 mL after reconstitution with 1.4 mL SWFI, USP.

    Arm title
    		 Omalizumab 300 mg
    Arm description
    		 Participants received at least one 300 mg omalizumab injection during the treatment period. Two participants were randomized to the Omalizumab 300 mg group; however, they received one dose of omalizumab 150 mg during the treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Omalizumab
    Investigational medicinal product code
    RO5489789
    Other name
    Xolair
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received 300 mg omalizumab subcutaneously on Day 1, Week 4, and Week 8, with 1.4 mL SWFI. Each omalizumab vial contained 202.5 mg omalizumab, 145.5 mg sucrose, 2.8 mg, L-histidine hydrochloride monohydrate, 1.8 mg L-histidine, and 0.5 mg polysorbate 20. Each vial was designed to deliver 150 mg of omalizumab in 1.2 mL after reconstitution with 1.4 mL SWFI, USP.

    Number of subjects in period 1
    		Placebo Omalizumab 75 mg Omalizumab 150 mg Omalizumab 300 mg
    Started
    79
    82
    82
    79
    Completed
    74
    75
    74
    67
    Not completed
    5
    7
    8
    12
         Consent withdrawn by subject
    3
    4
    2
    3
         Physician decision
    -
    1
    -
    -
         Disease progression
    -
    1
    3
    6
         Adverse event, non-fatal
    1
    -
    1
    1
         Lost to follow-up
    1
    1
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received only placebo injections (i.e., no active treatment)

    Reporting group title
    Omalizumab 75 mg
    Reporting group description
    		 Participants received at least one 75 mg omalizumab injection but no higher active dose level (150 mg or 300 mg) injections during the treatment period. Six participants were randomized to the Omalizumab 75 mg group received at least one dose of omalizumab 150 mg during the treatment period and were therefore included in the Omalizumab 150 mg group.

    Reporting group title
    Omalizumab 150 mg
    Reporting group description
    		 Participants who received at least one 150 mg omalizumab injection but no higher active dose level (300 mg) injections during the treatment period.

    Reporting group title
    Omalizumab 300 mg
    Reporting group description
    		 Participants received at least one 300 mg omalizumab injection during the treatment period. Two participants were randomized to the Omalizumab 300 mg group; however, they received one dose of omalizumab 150 mg during the treatment period.

    Reporting group values
    		 Placebo Omalizumab 75 mg Omalizumab 150 mg Omalizumab 300 mg Total
    Number of subjects
    		 79 82 82 79 322
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 2 4 2 2 10
        Adults (18-64 years)
    		 74 73 77 70 294
        From 65-84 years
    		 3 5 3 7 18
        85 years and over
    		 0 0 0 0 0
    Gender categorical
    The majority of participants were female.
    Units: Subjects
        Female
    		 55 61 65 63 244
        Male
    		 24 21 17 16 78

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received only placebo injections (i.e., no active treatment)

    Reporting group title
    Omalizumab 75 mg
    Reporting group description
    		 Participants received at least one 75 mg omalizumab injection but no higher active dose level (150 mg or 300 mg) injections during the treatment period. Six participants were randomized to the Omalizumab 75 mg group received at least one dose of omalizumab 150 mg during the treatment period and were therefore included in the Omalizumab 150 mg group.

    Reporting group title
    Omalizumab 150 mg
    Reporting group description
    		 Participants who received at least one 150 mg omalizumab injection but no higher active dose level (300 mg) injections during the treatment period.

    Reporting group title
    Omalizumab 300 mg
    Reporting group description
    		 Participants received at least one 300 mg omalizumab injection during the treatment period. Two participants were randomized to the Omalizumab 300 mg group; however, they received one dose of omalizumab 150 mg during the treatment period.

    Subject analysis set title
    Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    This population included participants who received at least one dose of either placebo or the study drug (omalizumab 75 mg/150 mg/ 300 mg according to the actual treatment received).

    Subject analysis set title
    Modified intent to treat population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Modified intent to treat (mITT) population included all participants randomized in the study who received at least one dose of study drug.

    Subject analysis set title
    Pharmacokinetic population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Pharmacokinetic (PK-evaluable) population included all randomized participants who received at least one dose of the study drug and had provided at least one serum sample for determination of omalizumab concentration.

    Primary: Mean change in weekly itch severity score from Baseline at Week 12

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    End point title
    		 Mean change in weekly itch severity score from Baseline at Week 12
    End point description
    Weekly itch severity score is a component of the urticaria activity score over 7 days (UAS7). Daily itch severity score is the average of the morning and evening scores with use of a scale of 0 (none) to 3 (severe). Weekly itch severity score is the sum of the daily scores over 7 days; thus, the weekly score represents pruritus (itch) severity on a scale from 0 (minimum) to 21 (maximum). Negative value indicated decrease in mean weekly itch severity score from the baseline in all treatment groups during the 28-week study period. Change from Baseline was defined as itch severity score at Week 12 minus the baseline score and was calculated using baseline observation carried forward (BOCF) method. This analysis was performed on mITT population.
    End point type
    Primary
    End point timeframe
    Baseline (Screening [Days -18 to -7]) and Week 12
    End point values
    		 Placebo Omalizumab 75 mg Omalizumab 150 mg Omalizumab 300 mg
    Number of subjects analysed
    79
    82
    82
    79
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    -5.14 ( 5.58 )
    -5.87 ( 6.45 )
    -8.14 ( 6.44 )
    -9.77 ( 5.95 )
    Statistical analysis title
    		 Change from Baseline in weekly itch severity score
    Comparison groups
    Placebo v Omalizumab 75 mg
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4637 [1]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.54
         upper limit
    		 1.16
    Notes
    [1] - ANCOVA t-test was used to derive the 'p-value'.
    Statistical analysis title
    		 Change from Baseline in weekly itch severity score
    Comparison groups
    Placebo v Omalizumab 150 mg
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0011 [2]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.85
         upper limit
    		 -1.24
    Notes
    [2] - ANCOVA t-test was used to derive the 'p-value'.
    Statistical analysis title
    		 Change from Baseline in weekly itch severity score
    Comparison groups
    Placebo v Omalizumab 300 mg
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [3]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -4.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.49
         upper limit
    		 -3.13
    Notes
    [3] - ANCOVA t-test was used to derive the 'p-value'.

    Secondary: Mean change from Baseline in urticaria activity score over 7 days at Week 12

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    End point title
    		 Mean change from Baseline in urticaria activity score over 7 days at Week 12
    End point description
    The UAS7 is a composite of recorded score with numeric severity intensity ratings for the number of wheals (hives); and the intensity of the itch, measured twice daily (morning and evening). It was measured on a scale of 0 (none ) to 3 (intense/severe) . Daily UAS is the average of morning and evening scores (range, 0−6 points/day) and the UAS7 is the sum of the daily UAS scores over 7 days (range, 0−42). Negative value indicated decrease in mean UAS from the baseline in all treatment groups during the 28-week study period. Change from Baseline was defined as urticaria activity score over 7 days at Week 12 minus the baseline score and was calculated using BOCF method. This analysis was performed on mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline (Screening [Days -18 to -7]) and Week 12
    End point values
    		 Placebo Omalizumab 75 mg Omalizumab 150 mg Omalizumab 300 mg
    Number of subjects analysed
    79
    82
    82
    79
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    -10.36 ( 11.61 )
    -13.08 ( 12.67 )
    -17.89 ( 13.23 )
    -21.74 ( 12.78 )
    Statistical analysis title
    		 Change from Baseline in UAS7 at Week 12
    Comparison groups
    Placebo v Omalizumab 75 mg
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1575
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.53
         upper limit
    		 1.07
    Statistical analysis title
    		 Change from Baseline in UAS7 at Week 12
    Comparison groups
    Placebo v Omalizumab 150 mg
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -7.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.49
         upper limit
    		 -3.88
    Statistical analysis title
    		 Change from Baseline in UAS 7 at Week 12
    Comparison groups
    Placebo v Omalizumab 300 mg
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -12.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.13
         upper limit
    		 -8.66

    Secondary: Mean change from Baseline in weekly number of hives score at Week 12

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    End point title
    		 Mean change from Baseline in weekly number of hives score at Week 12
    End point description
    Number of hives is measured twice daily (morning and evening), on a scale from 0 (none) to 3 (> 12 hives per 12 hours). Daily hives score is the average of morning and evening scores, and the weekly hives score is the sum of the daily hives scores over 7 days (range, 0−21). Change from Baseline was defined as itch severity score at Week 12 minus the baseline score and was calculated using BOCF method. This analysis was performed on mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline (Screening [Days -18 to -7]) and Week 12
    End point values
    		 Placebo Omalizumab 75 mg Omalizumab 150 mg Omalizumab 300 mg
    Number of subjects analysed
    79
    82
    82
    79
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    -5.22 ( 6.56 )
    -7.21 ( 6.96 )
    -9.75 ( 7.28 )
    -11.97 ( 7.58 )
    Statistical analysis title
    		 Change from Baseline in weekly number of hives
    Comparison groups
    Placebo v Omalizumab 75 mg
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0603
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.11
         upper limit
    		 0.09
    Statistical analysis title
    		 Change from Baseline in weekly number of hives
    Comparison groups
    Placebo v Omalizumab 150 mg
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -4.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.65
         upper limit
    		 -2.36
    Statistical analysis title
    		 Change from Baseline in weekly number of hives
    Comparison groups
    Placebo v Omalizumab 300 mg
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -7.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.26
         upper limit
    		 -4.93

    Secondary: Median time to minimally important difference response in the weekly itch severity score by Week 12

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    End point title
    		 Median time to minimally important difference response in the weekly itch severity score by Week 12
    End point description
    The minimally important difference (MID) response for weekly itch severity score was defined as a reduction from Baseline in weekly itch severity score of >= 5 points. The time to weekly itch severity score MID response was defined as the time (in weeks) from Day 1 to the study week when weekly itch severity score MID response was first achieved. This analysis was performed on mITT population.
    End point type
    Secondary
    End point timeframe
    Up to Week 12
    End point values
    		 Placebo Omalizumab 75 mg Omalizumab 150 mg Omalizumab 300 mg
    Number of subjects analysed
    79
    82
    82
    79
    Units: Number of weeks
        median (full range (min-max))
    4 (1 to 12)
    2 (0 to 12)
    2 (1 to 12)
    1 (1 to 12)
    Statistical analysis title
    		 Time to MID response in weekly itch severity score
    Comparison groups
    Placebo v Omalizumab 75 mg
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0478
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1
         upper limit
    		 2.05
    Statistical analysis title
    		 Time to MID response in weekly itch severity score
    Comparison groups
    Placebo v Omalizumab 150 mg
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0101
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.12
         upper limit
    		 2.26
    Statistical analysis title
    		 Time to MID response in weekly itch severity score
    Comparison groups
    Placebo v Omalizumab 300 mg
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    2.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.48
         upper limit
    		 3.03

    Secondary: Number of participants with urticaria activity score 7 less than or equal to 6 at Week 12

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    End point title
    		 Number of participants with urticaria activity score 7 less than or equal to 6 at Week 12
    End point description
    The UAS7 less than or equal to (<=) 6 identifies participants whose conditions are considered clinically well controlled. The UAS is a composite of recorded scores with numeric severity intensity ratings on a scale of 0 (none) to 3 (intense/severe) for analysis of the number of wheals (hives) and the intensity of the itch, measured twice daily (morning and evening). Daily UAS is the average of morning and evening scores (range, 0−6 points per day) and the UAS7 is the sum of the daily UAS scores over 7 days (range, 0−42). Baseline UAS7 was calculated using data from the 7 days prior to the first treatment date. A higher UAS indicated more urticaria activity. A negative change score indicated improvement. This analysis was performed on mITT population.
    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
    79
    82
    82
    79
    Units: Number of participants
    15
    22
    35
    52
    Statistical analysis title
    		 Participants with UAS7 <= 6 at Week 12
    Comparison groups
    Placebo v Omalizumab 75 mg
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3419
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    		 Participants with UAS7 <= 6 at Week 12
    Comparison groups
    Placebo v Omalizumab 150 mg
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.001
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    		 participants with UAS7 <= 6 at Week 12
    Comparison groups
    Placebo v Omalizumab 300 mg
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: Number of participants with minimally important difference in weekly itch severity score at Week 12

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    End point title
    		 Number of participants with minimally important difference in weekly itch severity score at Week 12
    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. The MID response for weekly itch severity score was defined as a reduction from Baseline in weekly itch severity score of 5 points or more. This outcome measure shows number of participants classified as MID responders at Week 12, meaning their weekly itch severity scores at Week 12 were at least 5 points lower than that at the Baseline. This analysis was performed on mITT population.
    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
    79
    82
    82
    79
    Units: Number of participants
    38
    46
    57
    62
    Statistical analysis title
    		 Participants with weekly itch score MID response
    Comparison groups
    Placebo v Omalizumab 75 mg
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.4366
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    		 Participants with weekly itch score MID Response
    Comparison groups
    Placebo v Omalizumab 150 mg
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0045
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    		 Participants with weekly itch score MID response
    Comparison groups
    Placebo v Omalizumab 300 mg
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: Mean change from Baseline in the weekly size of the largest hive score at Week 12

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    End point title
    		 Mean change from Baseline in the weekly size of the largest hive score at Week 12
    End point description
    The size of the largest hive is assessed twice daily (morning and evening) on a scale of largest hive score (LHC) as 0 (none) to 3 (> 2.5 cm). The daily score is the average of the morning and evening scores. The weekly size of the largest hive score is the sum of the daily scores over 7 days, and ranges from 0 to 21. The Baseline weekly size of the largest hive score is the sum of daily scores over the 7 days prior to the first treatment and was calculated using BOCF method. A higher score indicates larger hives. A negative change score indicates a reduction in hive size. This analysis was performed on mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline (Screening [Days -18 to -7]) and Week 12
    End point values
    		 Placebo Omalizumab 75 mg Omalizumab 150 mg Omalizumab 300 mg
    Number of subjects analysed
    79
    82
    82
    79
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    -4.04 ( 5.55 )
    -6.52 ( 6.33 )
    -7.84 ( 6.75 )
    -11 ( 7.18 )
    Statistical analysis title
    		 Change from Baseline in the weekly size of the LHC
    Comparison groups
    Placebo v Omalizumab 75 mg
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0082
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.32
         upper limit
    		 -0.65
    Statistical analysis title
    		 Change from Baseline in the weekly size of the LHC
    Comparison groups
    Placebo v Omalizumab 150 mg
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.61
         upper limit
    		 -1.9
    Statistical analysis title
    		 Change from Baseline in the weekly size of the LHC
    Comparison groups
    Placebo v Omalizumab 300 mg
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -7.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.03
         upper limit
    		 -5.27

    Secondary: Mean change from Baseline in the overall dermatology life quality index at Week 12

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    End point title
    		 Mean change from Baseline in the overall dermatology life quality index at Week 12
    End point description
    Dermatology life quality index (DLQI) is a 10-item dermatology-specific health-related quality of life measure. Participants rate 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 (high). 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. This analysis was performed on mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline (Screening [Days -18 to -7]) and Week 12
    End point values
    		 Placebo Omalizumab 75 mg Omalizumab 150 mg Omalizumab 300 mg
    Number of subjects analysed
    79
    82
    82
    79
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    -6.09 ( 7.47 )
    -7.5 ( 7.16 )
    8.29 ( 6.31 )
    -10.15 ( 6.83 )
    Statistical analysis title
    		 Change From Baseline in DLQI at Week 12
    Comparison groups
    Placebo v Omalizumab 75 mg
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1207
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.82
         upper limit
    		 0.45
    Statistical analysis title
    		 Change From Baseline in DLQI at Week 12
    Comparison groups
    Placebo v Omalizumab 150 mg
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0215 [4]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.64
         upper limit
    		 -0.38
    Notes
    [4] - p-value is derived from ANCOVA t-test.
    Statistical analysis title
    		 Change From Baseline in DLQI at Week 12
    Comparison groups
    Placebo v Omalizumab 300 mg
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0004
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.85
         upper limit
    		 -1.73

    Secondary: Mean percentage of angioedema-free days from Week 4 to Week 12

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    End point title
    		 Mean 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 a participant reported as angioedema-free 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. This analysis was performed on mITT population.
    End point type
    Secondary
    End point timeframe
    From Week 4 to Week 12
    End point values
    		 Placebo Omalizumab 75 mg Omalizumab 150 mg Omalizumab 300 mg
    Number of subjects analysed
    70 [5]
    71 [6]
    74 [7]
    74 [8]
    Units: Percentage of days
        arithmetic mean (standard deviation)
    89.2 ( 19 )
    93.5 ( 14.9 )
    91.6 ( 17.4 )
    95.5 ( 14.5 )
    Notes
    [5] - Data is presented for the participants available at the time of assessment.
    [6] - Data is presented for the participants available at the time of assessment.
    [7] - Data is presented for the participants available at the time of assessment.
    [8] - Data is presented for the participants available at the time of assessment.
    Statistical analysis title
    		 Percentage of angioedema-free days from W4 to W12
    Comparison groups
    Placebo v Omalizumab 75 mg
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1361
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 90
         upper limit
    		 97
    Statistical analysis title
    		 Percentage of angioedema-free days from W4 to W12
    Comparison groups
    Placebo v Omalizumab 150 mg
    Number of subjects included in analysis
    144
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0905
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 87.6
         upper limit
    		 95.6
    Statistical analysis title
    		 Percentage of angioedema-free days from W4 to W12
    Comparison groups
    Placebo v Omalizumab 300 mg
    Number of subjects included in analysis
    144
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 92.1
         upper limit
    		 98.8

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 28 weeks
    Adverse event reporting additional description
    Safety evaluable set: All randomized participants who received at least one dose of study drug (omalizumab or the placebo).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received only placebo injections (i.e., no active treatment)

    Reporting group title
    Omalizumab 75 mg
    Reporting group description
    		 Participants received at least one 75 mg omalizumab injection, but no higher active dose level (150 mg or 300 mg) injections during the treatment period. Six participants were randomized to the Omalizumab 75 mg group received at least one dose of omalizumab 150 mg during the treatment period and were therefore included in the Omalizumab 150 mg group.

    Reporting group title
    Omalizumab 150 mg
    Reporting group description
    		 Participants who received at least one 150 mg omalizumab injection but no higher active dose level (300 mg) injections during the treatment period.

    Reporting group title
    Omalizumab 300 mg
    Reporting group description
    		 Participants received at least one 300 mg omalizumab injection during the treatment period. Two participants were randomized to the Omalizumab 300 mg group; however, they received one dose of omalizumab 150 mg during the 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
    2 / 79 (2.53%)
    1 / 76 (1.32%)
    1 / 88 (1.14%)
    5 / 79 (6.33%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant melanoma in situ
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 76 (0.00%)
    0 / 88 (0.00%)
    1 / 79 (1.27%)
         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
    Surgical and medical procedures
    Tonsillectomy
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 76 (0.00%)
    0 / 88 (0.00%)
    1 / 79 (1.27%)
         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
    Haemorrhoids
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 76 (0.00%)
    0 / 88 (0.00%)
    0 / 79 (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
    Melaena
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 76 (0.00%)
    0 / 88 (0.00%)
    1 / 79 (1.27%)
         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
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 76 (1.32%)
    1 / 88 (1.14%)
    0 / 79 (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
    Idiopathic urticaria
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 76 (0.00%)
    1 / 88 (1.14%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 76 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (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
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 76 (0.00%)
    0 / 88 (0.00%)
    1 / 79 (1.27%)
         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
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 76 (0.00%)
    0 / 88 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    34 / 79 (43.04%)
    30 / 76 (39.47%)
    39 / 88 (44.32%)
    33 / 79 (41.77%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 79 (6.33%)
    4 / 76 (5.26%)
    16 / 88 (18.18%)
    8 / 79 (10.13%)
         occurrences all number
    5
    5
    20
    8
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    4 / 79 (5.06%)
    2 / 76 (2.63%)
    4 / 88 (4.55%)
    3 / 79 (3.80%)
         occurrences all number
    4
    2
    4
    5
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 79 (3.80%)
    4 / 76 (5.26%)
    2 / 88 (2.27%)
    2 / 79 (2.53%)
         occurrences all number
    3
    4
    2
    2
    Skin and subcutaneous tissue disorders
    Idiopathic urticaria
         subjects affected / exposed
    2 / 79 (2.53%)
    8 / 76 (10.53%)
    6 / 88 (6.82%)
    4 / 79 (5.06%)
         occurrences all number
    3
    8
    8
    5
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 79 (5.06%)
    1 / 76 (1.32%)
    1 / 88 (1.14%)
    4 / 79 (5.06%)
         occurrences all number
    4
    1
    1
    6
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    13 / 79 (16.46%)
    13 / 76 (17.11%)
    12 / 88 (13.64%)
    10 / 79 (12.66%)
         occurrences all number
    16
    16
    15
    15
    Upper respiratory tract infection
         subjects affected / exposed
    7 / 79 (8.86%)
    0 / 76 (0.00%)
    2 / 88 (2.27%)
    6 / 79 (7.59%)
         occurrences all number
    7
    0
    2
    8
    Influenza
         subjects affected / exposed
    4 / 79 (5.06%)
    5 / 76 (6.58%)
    3 / 88 (3.41%)
    2 / 79 (2.53%)
         occurrences all number
    4
    5
    3
    2
    Sinusitis
         subjects affected / exposed
    2 / 79 (2.53%)
    3 / 76 (3.95%)
    1 / 88 (1.14%)
    6 / 79 (7.59%)
         occurrences all number
    2
    4
    1
    6
    Bronchitis
         subjects affected / exposed
    2 / 79 (2.53%)
    4 / 76 (5.26%)
    0 / 88 (0.00%)
    3 / 79 (3.80%)
         occurrences all number
    2
    6
    0
    3
    Urinary tract infection
         subjects affected / exposed
    1 / 79 (1.27%)
    4 / 76 (5.26%)
    3 / 88 (3.41%)
    0 / 79 (0.00%)
         occurrences all number
    1
    5
    4
    0

    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
    The purpose of the protocol amendment on 11 January 2011 was to modify the study design according to recommendations by the FDA, internal Genentech staff, and external experts. Secondary objective was modified as to provide information about recurrence of disease after withdrawal of omalizumab in participants with refractory CIU. The second treatment period, including the re-randomization portion was removed, accordingly secondary end-points were modified. The planned number of participants within each treatment group were changed from 80 in the Omalizumab treatment group and 60 in the Placebo group to 75 per group. The screening period was modified from 14−18 to 12−18 days prior to Day 1. Post-hoc analyses were conducted on the number of participants who achieved a complete response (UAS7 = 0), at Week 12 and at Week 28.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/25046337
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