A Safety Study of Xolair (Omalizumab) in Patients With Chronic Idiopathic Urticaria (CIU) Who Remain Symptomatic Despite Treatment With H1 Antihistamines, H2 Blockers, and/or Leukotriene Receptor Antagonists

Study Overview
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Brief Summary
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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).

Official Title
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A Phase III, Multicenter, Randomized, Double-blind, Placebo-controlled Safety Study of Xolair (Omalizumab) in Patients With Chronic Idiopathic Urticaria (CIU) Who Remain Symptomatic Despite Treatment With H1 Antihistamines, H2 Blockers, and/or Leukotriene Receptor Antagonists

Conditions
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Chronic Idiopathic Urticaria

Intervention / Treatment
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* Drug: Omalizumab
* Drug: Placebo
* Drug: H1 antihistamine, H2 antihistamine, leukotriene receptor antagonist
* Drug: Diphenhydramine


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants received placebo subcutaneously every 4 weeks during the 24 week treatment period. | Drug: Placebo<br>* Placebo was supplied as a lyophilized, sterile powder in a single-use vial without study drug.<br>Drug: H1 antihistamine, H2 antihistamine, leukotriene receptor antagonist<br>* 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.<br>Drug: Diphenhydramine<br>* 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.<br>|
| Experimental: Omalizumab 300 mg<br>Participants received omalizumab 300 mg subcutaneously every 4 weeks during the 24 week treatment period. | Drug: Omalizumab<br>* Omalizumab was supplied as a lyophilized, sterile powder in a single-use vial.<br>* Other names: Xolair;Drug: H1 antihistamine, H2 antihistamine, leukotriene receptor antagonist<br>* 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.<br>Drug: Diphenhydramine<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline to the end of study (up to 40 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline to Week 12 | 
| 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. | Baseline to Week 12 | 
| 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. | Baseline to Week 12 | 
| 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. | Baseline to Week 12 | 
| 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. | Week 12 | 
| 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. | Baseline to Week 12 | 
| 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. | Baseline to Week 12 | 
| 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. | Baseline to Week 12 | 
| 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. | Week 4 to Week 12 | 
| 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. | Week 12 |