A Study to Evaluate the Efficacy, Response Duration and Safety of Xolair (Omalizumab) in Patients With Chronic Idiopathic Urticaria (CIU)/Chronic Spontaneous Urticaria (CSU) Who Remain Symptomatic Despite Antihistamine Treatment (H1)

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 efficacy and safety 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 refractory CIU and who remain symptomatic despite standard-dosed H1 antihistamine treatment.

Detailed Description
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The trial incorporated a Type I error control plan, as follows: The testing of the primary endpoint was conducted in the following hierarchical order. A p-value that is less than 0.05 can only be claimed statistically significant if statistical significance has been claimed at the previous stage. Stage 1: Omalizumab 300-mg group vs. placebo Stage 2: Omalizumab 150-mg group vs. placebo Stage 3: Omalizumab 75-mg group vs. placebo A hierarchical analysis of the secondary endpoints was performed for each dose found to be significant in the primary endpoint. A p-value that is less than 0.05 can only be claimed statistically significant if statistical significance has been claimed at the previous stage. Stage 1: Change from baseline in Urticaria Activity Score (UAS7) at Week 12 Stage 2: Change from baseline in the weekly number of hives score at Week 12 Stage 3: Time to weekly itch severity score Minimally Important Difference (MID) response at Week 12 Stage 4: Proportion of patients with UAS7 ≤ 6 at Week 12 Stage 5: Proportion of weekly itch severity score MID Responders at Week 12 Stage 6: Change from baseline in weekly size of the largest hive score at Week 12 Stage 7: Change from baseline in overall Dermatology Life Quality Index (DLQI) score at Week 12 Stage 8: Proportion of angioedema-free days from Week 4 to Week 12

Official Title
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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)/Chronic Spontaneous Urticaria Who Remain Symptomatic Despite Antihistamine Treatment (H1)

Conditions
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Chronic Idiopathic Urticaria

Intervention / Treatment
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* Drug: Placebo
* Drug: Omalizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of Chronic Idiopathic Urticaria (CIU)/Chronic Spontaneous Urticaria (CSU) CIU/CSU refractory to H1 antihistamines at the time of randomization. Exclusion Criteria: Treatment with an investigational agent within 30 days prior to screening. Weight < 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. Any H2 antihistamine use within 7 days prior to screening. Any leukotriene receptor antagonist (LTRA) (montelukast or zafirlukast) within 7 days prior to screening. Any H1 antihistamines at greater than approved doses within 3 days 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. Nursing women or women of childbearing potential, unless they meet the following definition of post-menopausal: 12 months of natural amenorrhea or 6 months of spontaneous amenorrhea with serum follicle-stimulating hormone (FSH) levels > 40 milli-international units per milliliter (mIU/mL) or 6 weeks post surgical bilateral oophorectomy (with or without hysterectomy) or hysterectomy or are using one or more of the following acceptable methods of contraception: surgical sterilization, hormonal contraception, and double-barrier methods.

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Placebo<br>Placebo subcutaneously (sc) every 4 weeks | Drug: Placebo<br>* Placebo was supplied lyophilized in vials.<br>Drug: Omalizumab<br>* Omalizumab was supplied lyophilized in vials.<br>* Other names: Xolair;|
| Experimental: Omalizumab 75 mg<br>Omalizumab 75 mg sc every 4 weeks | Drug: Omalizumab<br>* Omalizumab was supplied lyophilized in vials.<br>* Other names: Xolair;|
| Experimental: Omalizumab 150 mg<br>Omalizumab 150 mg sc every 4 weeks | Drug: Omalizumab<br>* Omalizumab was supplied lyophilized in vials.<br>* Other names: Xolair;|
| Experimental: Omalizumab 300 mg<br>Omalizumab 300 mg sc every 4 weeks. | Drug: Omalizumab<br>* Omalizumab was supplied lyophilized in vials.<br>* Other names: Xolair;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Weekly Itch Severity Score at 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. | Baseline, Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Weekly Urticaria Activity Score (UAS7) at Week 12 | The urticaria activity score (UAS) is a composite of scores on a scale of 0 (none) to 3 (intense/severe) for 1) the number of wheals (hives); and 2) the intensity of the itch, measured twice daily (morning and evening). Daily UAS is the average of morning and evening scores (ranging from 0-6) and the UAS7 is the sum of the daily UAS over 7 days (ranging from 0-42). Baseline UAS7 is calculated using data from the 7 days prior to the first treatment date. A higher UAS indicates more urticaria activity. A negative change score indicates improvement. | Baseline, Week 12 | 
| Change From Baseline in the Weekly Number of Hives Score at 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. | Baseline, Week 12 | 
| Time to Minimally Important Difference (MID) Response in the Weekly Itch Severity Score by 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. 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. 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. | by Week 12 | 
| Percentage of Participants With a UAS7 Less Than or Equal to 6 at Week 12 | The urticaria activity score (UAS) is a composite of scores on a scale of 0 (none) to 3 (intense/severe) for 1) the number of wheals (hives); and 2) the intensity of the itch, measured twice daily (morning and evening). Daily UAS is the average of morning and evening scores (ranging from 0-6) and the UAS7 is the sum of the daily UAS over 7 days (ranging from 0-42). Baseline UAS7 is calculated using data from the 7 days prior to the first treatment date. A higher UAS indicates more urticaria activity. A negative change score indicates improvement. | Week 12 | 
| Percentage of Weekly Itch Severity Score MID Responders at 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. 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 the percentage 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 at Baseline. | Baseline, Week 12 | 
| Change From Baseline in the Weekly Size of the Largest Hive Score at Week 12 | The size of the largest hive is assessed twice daily (morning and evening) on a scale of 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. A higher score indicates larger hives. A negative change score indicates a reduction in hive size. | Baseline, Week 12 | 
| Change From Baseline in the Overall Dermatology Life Quality Index (DLQI) at Week 12 | The 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 (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, 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 a patient 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. | Week 4 to Week 12 |