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

Study Overview
=================
Brief Summary
-----------------
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-dose H1 antihistamine treatment.

Detailed Description
-----------------
Type I Error Rate Control Plan Primary Outcome Measure In order to maintain an overall type I error rate of 0.05 (2-sided) across the 3 omalizumab dose levels, the testing of the primary Outcome Measure was conducted in the following hierarchical order. A p-value < 0.05 is only considered statistically significant if statistical significance was 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 Secondary Outcome Measures A hierarchical analysis of the following secondary Outcome Measures was performed for each dose found to be significant in the primary Outcome Measure. A p-value < 0.05 is only considered statistically significant if statistical significance was claimed at the previous stage. Stage 1: Change from baseline to Week 12 in the urticaria activity score over 7 days (UAS7) Stage 2: Change from Baseline to Week 12 in the weekly number of hives score Stage 3: Time to minimally important difference (MID) response in the weekly itch severity score by Week 12 Stage 4: Percentage of participants with a UAS7 score ≤ 6 at Week 12 Stage 5: Percentage of weekly itch severity score MID responders at Week 12 Stage 6: Change from Baseline to Week 12 in the weekly size of the largest hive score Stage 7: Change from Baseline in the overall dermatology life quality index (DLQI) score at Week 12 Stage 8: Change from Baseline in the overall dermatology life quality index (DLQI) score at Week 12 Stage 9: Percentage of complete responders (UAS7 = 0) at Week 12

Official Title
-----------------
A Phase III, Multicenter, Randomized, Double-blind, Placebo-controlled, Dose-ranging Study to Evaluate the Efficacy and Safety of Xolair® (Omalizumab) in Patients With Chronic Idiopathic Urticaria (CIU)/Chronic Spontaneous Urticaria (CSU) Who Remain Symptomatic Despite Antihistamine Treatment (H1)

Conditions
-----------------
Chronic Idiopathic Urticaria

Intervention / Treatment
-----------------
* Drug: Omalizumab
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosis of Chronic Idiopathic Urticaria (CIU)/Chronic Spontaneous Urticaria (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 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
-----------------
Minimum Age: 12 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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>|
| Experimental: Omalizumab 75 mg<br>Participants received omalizumab 75 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;|
| Experimental: Omalizumab 150 mg<br>Participants received omalizumab 150 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;|
| 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;|

What is the study measuring?
-----------------
Primary 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | Week 12 |