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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
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
     Physician decision
-
1
-
-
     Adverse event, non-fatal
1
-
1
1
     Consent withdrawn by subject
3
4
2
3
     Disease progression
-
1
3
6
     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
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
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
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
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
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
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
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
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
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%)
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
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
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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