Chronic Idiopathic Urticaria
Conditions
Brief summary
The study is a global Phase III, multicenter, randomized, double-blind, placebo controlled, parallel-group study to evaluate the safety and efficacy of omalizumab administered subcutaneously as an add-on therapy for the treatment of adolescent and adult patients aged 12-75 who have been diagnosed with chronic idiopathic urticaria (CIU) who remain symptomatic despite standard-dosed H1 antihistamine treatment (including doses up to 4 times above the approved dose level), H2 blockers, and/or leukotriene receptor antagonists (LTRA).
Interventions
DRUGOmalizumab
Omalizumab was supplied as a lyophilized, sterile powder in a single-use vial.
DRUGPlacebo
Placebo was supplied as a lyophilized, sterile powder in a single-use vial without study drug.
DRUGH1 antihistamine, H2 antihistamine, leukotriene receptor antagonist
Participants were required to maintain stable doses of their pre-randomization combination therapy with an H1 antihistamine and either an H2 blocker or leukotriene receptor antagonist, or all 3 drugs in combination, throughout the 24-week treatment period and 16-week follow-up period of the 40-week study.
DRUGDiphenhydramine
Participants were provided with diphenhydramine 25 mg for itch relief on an as-needed basis, up to a maximum of 3 doses within 24 hours for the duration of the 40-week study.
Sponsors
Genentech, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of chronic idiopathic urticaria (CIU) refractory to H1 antihistamines, H2 blockers, and/or leukotriene receptor antagonists (LTRA) at the time of randomization. * The presence of itch and hives for \> 6 consecutive weeks at any time prior to enrollment despite current use of H1 antihistamine (up to 4 times the approved dosage), H2 blocker, and/or LTRA treatment during this time. * Urticaria activity score over 7 days (UAS7) score (range 0-42) ≥ 16 and itch component of UAS7 (range 0-21) ≥ 8 during 7 days prior to randomization (Week 0). * In-clinic UAS ≥ 4 on at least one of the screening visit days (Day -14, Day -7, or Day 1). * For women of childbearing potential, agreement to use an acceptable form of contraception and to continue its use for the duration of the study.
Exclusion criteria
* Treatment with an investigational agent within 30 days prior to screening. * Weight less than 20 kg (44 lbs). * Clearly defined underlying etiology for chronic urticarias other than CIU. * Evidence of parasitic infection. * Atopic dermatitis, bullous pemphigoid, dermatitis herpetiformis, senile pruritus, or other skin disease associated with itch. * Previous treatment with omalizumab within a year prior to screening. * Routine doses of the following medications within 30 days prior to screening: Systemic or cutaneous (topical) corticosteroids (prescription or over the counter), hydroxychloroquine, methotrexate, cyclosporine, or cyclophosphamide. * Intravenous (IV) immunoglobulin G (IVIG), or plasmapheresis within 30 days prior to screening. * Regular (daily/every other day) doxepin (oral) use within 6 weeks prior to screening. * Patients with current malignancy, history of malignancy, or currently under work-up for suspected malignancy except non-melanoma skin cancer that has been treated or excised and is considered resolved. * Hypersensitivity to omalizumab or any component of the formulation. * History of anaphylactic shock. * Presence of clinically significant cardiovascular, neurological, psychiatric, metabolic, or other pathological conditions that could interfere with the interpretation of the study results and or compromise the safety of the patients. * Evidence of current drug or alcohol abuse.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Adverse Events | Baseline to the end of study (up to 40 weeks) | The percentage of participants with serious adverse events and other adverse events is summarized by MedDRA preferred terms and organ classes in the Reported Adverse Events section below. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 12 in the Urticaria Activity Score Over 7 Days (UAS7) | Baseline to Week 12 | The UAS7 is the sum of the daily urticarial activity scores over 7 days and ranges from 0 to 42. The daily urticarial activity score is the average of the morning and evening urticarial activity scores and ranges from 0 to 6. The urticarial activity score is the sum of ratings on a scale of 0 to 3 (0=none to 3=intense/severe) for (1) the number of wheals (hives) and (2) itch intensity over the previous 12 hours, ranges from 0 to 6, and is measured twice daily (morning and evening). The Baseline score is the sum of the daily urticarial activity scores over the 7 days prior to the first treatment. A higher urticarial activity score indicates more urticaria activity. A negative change score indicates improvement. |
| Change From Baseline to Week 12 in the Weekly Number of Hives Score | Baseline to Week 12 | The weekly hives score is the sum of the daily hives scores over 7 days and ranges from 0 to 21. The number of hives is measured twice daily (morning and evening) on a scale of 0 (none) to 3 (\> 12 hives per 12 hours). The daily hives score is the average of the morning and evening scores. The Baseline score is the sum of the daily hives scores over the 7 days prior to the first treatment. A higher score indicates more hives. A negative change score indicates improvement. |
| Time to Minimally Important Difference (MID) Response in the Weekly Itch Severity Score by Week 12 | Baseline to Week 12 | The time to the MID response is the number of weeks from the start of treatment (Baseline) until the time point at which the first MID response occurs. The MID response is defined as a reduction ≥ 5 points from Baseline in the weekly itch severity score. The weekly itch severity score is the sum of the daily itch severity scores over 7 days and ranges from 0 to 21. The daily itch severity score is the average of the morning and evening scores on a scale of 0 (none) to 3 (severe). The Baseline weekly itch severity score is the sum of the daily itch severity scores over the 7 days prior to the first treatment. A higher itch severity score indicates more severe itching. |
| Percentage of Participants With a UAS7 Score ≤ 6 at Week 12 | Week 12 | The UAS7 is the sum of the daily urticarial activity scores over 7 days and ranges from 0 to 42. The daily urticarial activity score is the average of the morning and evening urticarial activity scores and ranges from 0 to 6. The urticarial activity score is the sum of ratings on a scale of 0 to 3 (0=none to 3=intense/severe) for (1) the number of wheals (hives) and (2) itch intensity over the previous 12 hours, ranges from 0 to 6, and is measured twice daily (morning and evening). The Baseline score is the sum of the daily urticarial activity scores over the 7 days prior to the first treatment. A higher urticarial activity score indicates more urticaria activity. |
| Change From Baseline to Week 12 in the Weekly Itch Severity Score | Baseline to Week 12 | 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. |
| Change From Baseline to Week 12 in the Weekly Size of the Largest Hive Score | Baseline to Week 12 | The weekly size of the largest hive score is the sum of the daily size of the largest hive scores over 7 days and ranges from 0 to 21. The daily size of the largest hive score is assessed twice daily (morning and evening) on a scale of 0 (none) to 3 (\> 2.5 cm). The daily size of the largest hive score is the average of the morning and evening scores. The Baseline weekly size of the largest hive score is calculated over the 7 days prior to the first treatment. A higher score indicates larger hives. A negative change score indicates a reduction in hive size. |
| Change From Baseline in the Overall Dermatology Life Quality Index (DLQI) Score at Week 12 | Baseline to Week 12 | The DLQI is a 10-item dermatology-specific health-related quality of life measure. Patients rated their dermatology symptoms as well as the impact of their skin condition on various aspects of their lives on a scale of 0 (Not at all) to 3 (Very much). The overall DLQI is the sum of the responses to the 10 items and ranges from 0 to 30. A lower score indicates a better quality of life. A negative change score indicates improvement. |
| Percentage of Angioedema-free Days From Week 4 to Week 12 | Week 4 to Week 12 | The percentage of angioedema-free days from Weeks 4 to 12 was defined as the number of days for which a patient responded No to the angioedema question in the daily diary divided by the total number of days with a non-missing diary entry, starting at the Week 4 visit and ending the day prior to the Week 12 visit. |
| Percentage of Complete Responders (UAS7 = 0) at Week 12 | Week 12 | A complete responder was defined as a participant with a UAS7 score = 0 at Week 12. The UAS7 is the sum of the daily urticarial activity scores over 7 days and ranges from 0 to 42. The daily urticarial activity score is the average of the morning and evening urticarial activity scores and ranges from 0 to 6. The urticarial activity score is the sum of ratings on a scale of 0 to 3 (0=none to 3=intense/severe) for (1) the number of wheals (hives) and (2) itch intensity over the previous 12 hours, ranges from 0 to 6, and is measured twice daily (morning and evening). The Baseline score is the sum of the daily urticarial activity scores over the 7 days prior to the first treatment. A higher urticarial activity score indicates more urticaria activity. |
| Percentage of Weekly Itch Severity Score MID Responders at Week 12 | Baseline to Week 12 | The percentage of participants with an itch severity score at 12 Weeks at least 5 points lower than at Baseline. The weekly itch severity score is the sum of the daily itch severity scores over 7 days and ranges from 0 to 21. The daily itch severity score is the average of the morning and evening scores on a scale of 0 (none) to 3 (severe). The Baseline weekly itch severity score is the sum of the daily itch severity scores over the 7 days prior to the first treatment. A higher itch severity score indicates more severe itching. |
Countries
Australia, Germany, New Zealand, Poland, Singapore, Switzerland, United Kingdom, United States
Participant flow
Pre-assignment details
Randomized population: All randomized participants regardless of whether they received any study drug. One patient in the placebo group was withdrawn after randomization but before receiving treatment due to an adverse event. This patient is 1 of 18 in this reporting group who did not complete the study.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo subcutaneously every 4 weeks during the 24 week treatment period. | 83 |
| Omalizumab 300 mg Participants received omalizumab 300 mg subcutaneously every 4 weeks during the 24 week treatment period. | 252 |
| Total | 335 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 3 |
| Overall Study | Disease Progression | 8 | 11 |
| Overall Study | Lost to Follow-up | 0 | 3 |
| Overall Study | Patient/Guardian Decision | 8 | 10 |
| Overall Study | Physician Decision | 1 | 1 |
Baseline characteristics
| Characteristic | Placebo | Omalizumab 300 mg | Total |
|---|---|---|---|
| Age Continuous | 44.3 years STANDARD_DEVIATION 14.7 | 42.7 years STANDARD_DEVIATION 13.9 | 43.1 years STANDARD_DEVIATION 14.1 |
| Sex: Female, Male Female | 55 Participants | 186 Participants | 241 Participants |
| Sex: Female, Male Male | 28 Participants | 66 Participants | 94 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 41 / 83 | 142 / 252 |
| serious Total, serious adverse events | 5 / 83 | 18 / 252 |
Outcome results
Primary
Percentage of Participants With Adverse Events
The percentage of participants with serious adverse events and other adverse events is summarized by MedDRA preferred terms and organ classes in the Reported Adverse Events section below.
Time frame: Baseline to the end of study (up to 40 weeks)
Population: Safety population: All randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Adverse Events | 78.3 Percentage of participants |
| Omalizumab 300 mg | Percentage of Participants With Adverse Events | 83.7 Percentage of participants |
Secondary
Change From Baseline in the Overall Dermatology Life Quality Index (DLQI) Score at Week 12
The DLQI is a 10-item dermatology-specific health-related quality of life measure. Patients rated their dermatology symptoms as well as the impact of their skin condition on various aspects of their lives on a scale of 0 (Not at all) to 3 (Very much). The overall DLQI is the sum of the responses to the 10 items and ranges from 0 to 30. A lower score indicates a better quality of life. A negative change score indicates improvement.
Time frame: Baseline to Week 12
Population: Modified intent-to-treat population: All randomized patients who received at least 1 dose of study drug and who had a DLQI score at Week 12.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in the Overall Dermatology Life Quality Index (DLQI) Score at Week 12 | -5.11 Units on a scale | Standard Deviation 7.53 |
| Omalizumab 300 mg | Change From Baseline in the Overall Dermatology Life Quality Index (DLQI) Score at Week 12 | -9.69 Units on a scale | Standard Deviation 6.85 |
Comparison: The null hypothesis was that there was no difference between the placebo and the omalizumab 300 mg groups.p-value: <0.000195% CI: [-6.28, -3.06]ANCOVA
Secondary
Change From Baseline to Week 12 in the Urticaria Activity Score Over 7 Days (UAS7)
The UAS7 is the sum of the daily urticarial activity scores over 7 days and ranges from 0 to 42. The daily urticarial activity score is the average of the morning and evening urticarial activity scores and ranges from 0 to 6. The urticarial activity score is the sum of ratings on a scale of 0 to 3 (0=none to 3=intense/severe) for (1) the number of wheals (hives) and (2) itch intensity over the previous 12 hours, ranges from 0 to 6, and is measured twice daily (morning and evening). The Baseline score is the sum of the daily urticarial activity scores over the 7 days prior to the first treatment. A higher urticarial activity score indicates more urticaria activity. A negative change score indicates improvement.
Time frame: Baseline to Week 12
Population: Modified intent-to-treat population: All randomized patients who received at least 1 dose of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 12 in the Urticaria Activity Score Over 7 Days (UAS7) | -8.50 Units on a scale | Standard Deviation 11.71 |
| Omalizumab 300 mg | Change From Baseline to Week 12 in the Urticaria Activity Score Over 7 Days (UAS7) | -19.01 Units on a scale | Standard Deviation 13.15 |
Comparison: The null hypothesis was that there was no difference between the placebo and the omalizumab 300 mg groups.p-value: <0.000195% CI: [-13.17, -6.86]ANCOVA
Secondary
Change From Baseline to Week 12 in the Weekly Itch Severity Score
The weekly itch severity score is the sum of the daily itch severity scores over 7 days and ranges from 0 to 21. The daily itch severity score is the average of the morning and evening scores on a scale of 0 (none) to 3 (severe). The Baseline weekly itch severity score is the sum of the daily itch severity scores over the 7 days prior to the first treatment. A higher itch severity score indicates more severe itching. A negative change score indicates improvement.
Time frame: Baseline to Week 12
Population: Modified intent-to-treat population: All randomized patients who received at least 1 dose of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 12 in the Weekly Itch Severity Score | -4.01 Units on a scale | Standard Deviation 5.87 |
| Omalizumab 300 mg | Change From Baseline to Week 12 in the Weekly Itch Severity Score | -8.55 Units on a scale | Standard Deviation 6.01 |
Comparison: The null hypothesis was that there was no difference between the placebo and the omalizumab 300 mg groups.p-value: <0.000195% CI: [-5.97, -3.08]ANCOVA
Secondary
Change From Baseline to Week 12 in the Weekly Number of Hives Score
The weekly hives score is the sum of the daily hives scores over 7 days and ranges from 0 to 21. The number of hives is measured twice daily (morning and evening) on a scale of 0 (none) to 3 (\> 12 hives per 12 hours). The daily hives score is the average of the morning and evening scores. The Baseline score is the sum of the daily hives scores over the 7 days prior to the first treatment. A higher score indicates more hives. A negative change score indicates improvement.
Time frame: Baseline to Week 12
Population: Modified intent-to-treat population: All randomized patients who received at least 1 dose of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 12 in the Weekly Number of Hives Score | -4.49 Units on a scale | Standard Deviation 6.33 |
| Omalizumab 300 mg | Change From Baseline to Week 12 in the Weekly Number of Hives Score | -10.46 Units on a scale | Standard Deviation 7.74 |
Comparison: The null hypothesis was that there was no difference between the placebo and the omalizumab 300 mg groups.p-value: <0.000195% CI: [-7.72, -4.07]ANCOVA
Secondary
Change From Baseline to Week 12 in the Weekly Size of the Largest Hive Score
The weekly size of the largest hive score is the sum of the daily size of the largest hive scores over 7 days and ranges from 0 to 21. The daily size of the largest hive score is assessed twice daily (morning and evening) on a scale of 0 (none) to 3 (\> 2.5 cm). The daily size of the largest hive score is the average of the morning and evening scores. The Baseline weekly size of the largest hive score is calculated over the 7 days prior to the first treatment. A higher score indicates larger hives. A negative change score indicates a reduction in hive size.
Time frame: Baseline to Week 12
Population: Modified intent-to-treat population: All randomized patients who received at least 1 dose of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 12 in the Weekly Size of the Largest Hive Score | -3.09 Units on a scale | Standard Deviation 5.46 |
| Omalizumab 300 mg | Change From Baseline to Week 12 in the Weekly Size of the Largest Hive Score | -8.82 Units on a scale | Standard Deviation 7.23 |
Comparison: The null hypothesis was that there was no difference between the placebo and the omalizumab 300 mg groups.p-value: <0.000195% CI: [-7.25, -3.96]ANCOVA
Secondary
Percentage of Angioedema-free Days From Week 4 to Week 12
The percentage of angioedema-free days from Weeks 4 to 12 was defined as the number of days for which a patient responded No to the angioedema question in the daily diary divided by the total number of days with a non-missing diary entry, starting at the Week 4 visit and ending the day prior to the Week 12 visit.
Time frame: Week 4 to Week 12
Population: Modified intent-to-treat population: All randomized patients who received at least 1 dose of study drug. Patients who withdrew before the Week 4 visit or who had missing responses for more than 40% of the daily diary entries between the Week 4 visit and the Week 12 visit were not included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percentage of Angioedema-free Days From Week 4 to Week 12 | 88.1 Percentage of days | Standard Deviation 18.9 |
| Omalizumab 300 mg | Percentage of Angioedema-free Days From Week 4 to Week 12 | 91.0 Percentage of days | Standard Deviation 21 |
Comparison: The null hypothesis was that there was no difference between the placebo and the omalizumab 300 mg groups.p-value: 0.0006Stratified Wilcoxon
Secondary
Percentage of Complete Responders (UAS7 = 0) at Week 12
A complete responder was defined as a participant with a UAS7 score = 0 at Week 12. The UAS7 is the sum of the daily urticarial activity scores over 7 days and ranges from 0 to 42. The daily urticarial activity score is the average of the morning and evening urticarial activity scores and ranges from 0 to 6. The urticarial activity score is the sum of ratings on a scale of 0 to 3 (0=none to 3=intense/severe) for (1) the number of wheals (hives) and (2) itch intensity over the previous 12 hours, ranges from 0 to 6, and is measured twice daily (morning and evening). The Baseline score is the sum of the daily urticarial activity scores over the 7 days prior to the first treatment. A higher urticarial activity score indicates more urticaria activity.
Time frame: Week 12
Population: Modified intent-to-treat population: All randomized patients who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Complete Responders (UAS7 = 0) at Week 12 | 4.8 Percentage of participants |
| Omalizumab 300 mg | Percentage of Complete Responders (UAS7 = 0) at Week 12 | 33.7 Percentage of participants |
Comparison: The null hypothesis was that there was no difference between the placebo and the omalizumab 300 mg groups.p-value: <0.0001Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With a UAS7 Score ≤ 6 at Week 12
The UAS7 is the sum of the daily urticarial activity scores over 7 days and ranges from 0 to 42. The daily urticarial activity score is the average of the morning and evening urticarial activity scores and ranges from 0 to 6. The urticarial activity score is the sum of ratings on a scale of 0 to 3 (0=none to 3=intense/severe) for (1) the number of wheals (hives) and (2) itch intensity over the previous 12 hours, ranges from 0 to 6, and is measured twice daily (morning and evening). The Baseline score is the sum of the daily urticarial activity scores over the 7 days prior to the first treatment. A higher urticarial activity score indicates more urticaria activity.
Time frame: Week 12
Population: Modified intent-to-treat population: All randomized patients who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With a UAS7 Score ≤ 6 at Week 12 | 12.0 Percentage of participants |
| Omalizumab 300 mg | Percentage of Participants With a UAS7 Score ≤ 6 at Week 12 | 52.4 Percentage of participants |
Comparison: The null hypothesis was that there was no difference between the placebo and the omalizumab 300 mg groups.p-value: <0.0001Cochran-Mantel-Haenszel
Secondary
Percentage of Weekly Itch Severity Score MID Responders at Week 12
The percentage of participants with an itch severity score at 12 Weeks at least 5 points lower than at Baseline. The weekly itch severity score is the sum of the daily itch severity scores over 7 days and ranges from 0 to 21. The daily itch severity score is the average of the morning and evening scores on a scale of 0 (none) to 3 (severe). The Baseline weekly itch severity score is the sum of the daily itch severity scores over the 7 days prior to the first treatment. A higher itch severity score indicates more severe itching.
Time frame: Baseline to Week 12
Population: Modified intent-to-treat population: All randomized patients who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Weekly Itch Severity Score MID Responders at Week 12 | 39.8 Percentage of participants |
| Omalizumab 300 mg | Percentage of Weekly Itch Severity Score MID Responders at Week 12 | 69.8 Percentage of participants |
Comparison: The null hypothesis was that there was no difference between the placebo and the omalizumab 300 mg groups.p-value: <0.0001Cochran-Mantel-Haenszel
Secondary
Time to Minimally Important Difference (MID) Response in the Weekly Itch Severity Score by Week 12
The time to the MID response is the number of weeks from the start of treatment (Baseline) until the time point at which the first MID response occurs. The MID response is defined as a reduction ≥ 5 points from Baseline in the weekly itch severity score. The weekly itch severity score is the sum of the daily itch severity scores over 7 days and ranges from 0 to 21. The daily itch severity score is the average of the morning and evening scores on a scale of 0 (none) to 3 (severe). The Baseline weekly itch severity score is the sum of the daily itch severity scores over the 7 days prior to the first treatment. A higher itch severity score indicates more severe itching.
Time frame: Baseline to Week 12
Population: Modified intent-to-treat population: All randomized patients who received at least 1 dose of study drug. Only patients with a MID response were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to Minimally Important Difference (MID) Response in the Weekly Itch Severity Score by Week 12 | 5.0 Weeks |
| Omalizumab 300 mg | Time to Minimally Important Difference (MID) Response in the Weekly Itch Severity Score by Week 12 | 2.0 Weeks |
Comparison: The null hypothesis was that there was no difference between the placebo and the omalizumab 300 mg groups.p-value: <0.000195% CI: [1.47, 2.68]Cox proportional hazards model