Mode of Action Study of Omalizumab in Patients With Chronic Idiopathic Urticaria (CIU) Who Fail to Respond to Antihistamine Treatment

Study Overview
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Brief Summary
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The study is designed to explore the mode of action for omalizumab therapy in patients with chronic idiopathic urticaria.

Official Title
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A Phase II, Multi-centre, Randomized, Double Blind, Placebo-controlled Study to Determine the Mode of Action of Omalizumab in Patients With Chronic Idiopathic Urticaria (CIU) Who Remain Symptomatic With Antihistamine Treatment (H1)

Conditions
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Chronic Idiopathic Urticaria

Intervention / Treatment
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* Drug: IGE025
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of chronic spontaneous urticaria refractory to H1 antihistamines at Baseline Exclusion Criteria: Clearly defined underlying etiology for chronic urticarias other than CIU (main manifestation being physical urticaria). This includes the following urticarias: Acute, solar, cholinergic, heat, cold, aquagenic, delayed pressure or contact, as well as the following diseases as these diseases may have symptoms of urticaria or angioedema: Urticarial vasculitis, urticaria pigmentosa, erythema multiforme, mastocytosis, hereditary or acquired angioedema, lymphoma, leukemia, or generalized cancer. Previous treatment with omalizumab. A history or presence of atopic dermatitis, bullous pemphigoid, dermatitis herpetiformis, senile pruritus or other skin disease associated with itch. Other protocol-defined inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 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: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IGE025<br>Patients will receive omalizumab administered subcutaneously every 4 weeks at the study center. | Drug: IGE025<br>* Study medication will be supplied as a lyophilized, sterile powder in a single-use, 5-mL vial.<br>|
| Placebo Comparator: Placebo to IGE025<br>Placebo administered subcutaneously every 4 weeks at the study center. | Drug: placebo<br>* Study medication will be supplied as a lyophilized, sterile powder in a single-use, 5-mL vial.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Observed Values and Absolute Change From Baseline in FceRI Positive Skin Cells: Dermis, Lesional and Non Lesional Skin | Observed values and absolute change in FcεRI positive skin cells: dermis non-lesional and lesional. The primary variable for this study was the relative change from baseline in the high affinity IgE receptor (FcεRI) positive skin cells, based on skin biopsies collected from patients with CIU after 12 weeks of treatment.The values are average of cell numbers derived from counting 5 consecutive microscopic fields. Area counted is 5x 0.196 mm2 | Baseline through Day 85 post-treatment | 
| Observed Values and Absolute Change From Baseline in IgE Positive Skin Cells: Dermis, Lesional and Non Lesional Skin | Observed values and absolute change in IgE positive skin cells: dermis non-lesional and lesional The primary variable for this study was the relative change from baseline in IgE positive skin cells, based on skin biopsies collected from patients with CIU after 12 weeks of treatment. The values are average of cell numbers derived from counting 5 consecutive microscopic fields. Area counted is 5x 0.196 mm2 | Baseline through Day 85 post-treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlation of Change From Baseline in IgE Receptor FceRI With Change From Baseline in UAS7 at Week 12 by Treatment, Skin Layer and Lesion Status | Correlation of primary endpoint with The UAS7 which is a composite eDiary-recorded score with numeric severity intensity ratings on a scale of 0-3 (0 = none to 3 = intense/severe) for 1) the number of wheals (hives); and 2) the intensity of the itch. The daily UAS is the average of the morning and evening scores and the UAS7 is the sum of the daily UAS scores over 7 days.UAS7 score: The sum of the daily UAS scores over 7 days. Range: 0-42. If fewer than 7 but at least 4 daily values were non-missing, the remaining values were imputed to be the average. This is equivalent to multiplying the average of the non missing values by 7. UAS7 score: The sum of the daily UAS scores over 7 days. Range: 0-42. A higher score indicates worse disease. | Baseline through Day 85 | 
| Correlation of Change From Baseline in IgE on Positive Skin Cells With Change From Baseline in UAS7 at Week 12 by Treatment, Skin Layer and Lesion Status | Correlation of primary endpoint with The UAS7 which is a composite eDiary-recorded score with numeric severity intensity ratings on a scale of 0-3 (0 = none to 3 = intense/severe) for 1) the number of wheals (hives); and 2) the intensity of the itch. The daily UAS is the average of the morning and evening scores and the UAS7 is the sum of the daily UAS scores over 7 days.UAS7 score: The sum of the daily UAS scores over 7 days. Range: 0-42. If fewer than 7 but at least 4 daily values were non-missing, the remaining values were imputed to be the average. This is equivalent to multiplying the average of the non missing values by 7. UAS7 score: The sum of the daily UAS scores over 7 days. Range: 0-42. A higher score indicates worse disease. | Baseline through Day 85 | 
| Observed Values and Absolute Change From Baseline in Skin Cell Subsets (CD3, CD4, CD8, Eosinophils, DCs, and Mast Cells) by Parameter, Skin Layer, Lesion Status, Treatment and Visit | The average number of cells derived from counting 5 consecutive microscopic fields. Area counted is 5x 0.196 mm2 | Baseline to Day 85 | 
| Observed Values From Baseline Through End of Study of Serum Chemkines or Histamine in Peripheral Blood Cells by Parameter, Treatment and Visit |  | Baseline through Day 85 | 
| Observed Values and Change From Baseline in Peripheral Blood Cell Subsets (FACS Parameters) at Week 12 (Day 85) by Treatment (PD Analysis Set) Measured as % Out of Leukocytes. | Fluorescence-activated cell sorting (FACS) is a specialized type of flow cytometry that provides a method for sorting a heterogeneous mixture of biological cells into two or more containers, one cell at a time, based upon the specific light scattering and fluorescent characteristics of each cell. (FACS) provides fast, objective and quantitative recording of fluorescent signals from individual cells as well as physical separation of cells of particular interest. A wide range of fluorophores can be used as labels in flow cytometry. Fluorophores are typically attached to an antibody that recognizes a target feature on or in the cell; they may also be attached to a chemical entity with affinity for the cell membrane or another cellular structure. Each fluorophore has a characteristic peak excitation and emission wavelength. | Baseline through Day 85 | 
| Observed Values and Change From Baseline in Peripheral Blood Cell Subsets (FACS Parameters) at Week 12 (Day 85) by Treatment (PD Analysis Set) Measured in Fluorescence Units. | Fluorescence-activated cell sorting (FACS) is a specialized type of flow cytometry that provides a method for sorting a heterogeneous mixture of biological cells into two or more containers, one cell at a time, based upon the specific light scattering and fluorescent characteristics of each cell. (FACS) provides fast, objective and quantitative recording of fluorescent signals from individual cells as well as physical separation of cells of particular interest. A wide range of fluorophores can be used as labels in flow cytometry. Fluorophores are typically attached to an antibody that recognizes a target feature on or in the cell; they may also be attached to a chemical entity with affinity for the cell membrane or another cellular structure. Each fluorophore has a characteristic peak excitation and emission wavelength. | Baseline through Day 85 | 
| Comparison of Baseline PD Parameters Between Healthy Volunteers and Urticaria Patients by Skin Layer Pharmacodynamic Analysis Set | The # positive cell values are average of cell numbers derived from counting 5 consecutive microscopic fields. Area counted is 5x 0.196 mm2 | Baseline | 
| Serum Levels of Omalizumab | Serum concentrations (ng/mL) of omalizumab by visit after the administration of omalizumab 300 mg every 4 weeks | Baseline through Day 85 | 
| Mean (SD) Serum Total IgE Concentration From Baseline by Visit |  | Baseline through Day 85 | 
| Mean (SD) Serum Total IgE % Change From Baseline by Visit |  | Baseline through Day 85 | 
| Mean (SD) Serum Free IgE Concentration From Baseline by Visit |  | Baseline through Day 85 | 
| Mean (SD) Serum Free IgE % Change From Baseline by Visit |  | Baseline through Day 85 | 
| Summary Statistics of Observed Values and Absolute Change From Baseline in Specific IgE Against Allergens and Bacterial Antigens by Parameter, Treatment and Visit |  | Baseline through Day 140 | 
| Change From Baseline in Urticaria Activity Score (UAS7) | Efficacy was assessed by the urticaria activity score (UAS). UAS was completed each morning and evening on a daily basis to record patient symptoms of itch and hives via an electronic diary. The UAS is a composite eDiary-recorded score with numeric severity intensity ratings on a scale of 0-3 (0 = none to 3 = intense/severe) for 1) the number of wheals (hives); and 2) the intensity of the itch. The daily UAS is the average of the morning and evening scores and the UAS7 is the sum of the daily UAS scores over 7 days.UAS7 score: The sum of the daily UAS scores over 7 days. Range: 0-42. If fewer than 7 but at least 4 daily values were non-missing, the remaining values were imputed to be the average. This is equivalent to multiplying the average of the non missing values by 7. UAS7 score: The sum of the daily UAS scores over 7 days. Range: 0-42. A higher score indicates worse disease. A negative change score (Week 12 score minus Baseline score) indicates improvement. | Baseline, Day 85 | 
| Likert Scale-Physician's and Patients In-clinic Global Assessment by Treatment | The investigator or the person he or she designated and the patient provided scoring of the patient's global assessment of symptoms (urticaria lesions (hives) and pruritus) reflective of the patient's condition over the 12 hours prior to the visit (0 = no symptoms, 1 = mild, 2 = moderate 3 = severe | Baseline, Day 85 | 
| Percentage of Angioedema-free Days Weeks 4 Through 12 by Treatment |  | Day 29 to Day 85 | 
| Change From Baseline in Dermatology Life Quality Index (DLQI) by Treatment | 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. An overall score was calculated as well as for the following domains: Symptoms and Feelings, Daily Activities, Leisure, Work and School, Personal Relationships, Treatment.Negative score shows positive efficacy. Meaning of DLQI Scores 0-1 = no effect at all on patient's life 2-5 = small effect on patient's life 6-10 = moderate effect on patient's life 11-20 = very large effect on patient's life 21-30 = extremely large effect on patient's life. The DLQI is calculated by summing the score of each question resulting in a maximum of 30 and a minimum of 0. The higher the score, the more quality of life is impaired. The DLQI can also be expressed as a percentage of the maximum possible score of 30. | Baseline through Day 85 | 
| Skindex-29 by Treatment | The Skindex-29 is a validated 29-item instrument to measure the effects of skin disease on patients' quality of life.Results are reported as 3 scale scores (functioning, emotions and symptoms) and a composite score (average scale score). The domain scores and the overall score are expressed on a 100-point scale, with higher scores indicating a lower level of quality of life. The cuttoff values for each category are noted below. Symtoms; 39 mild, 42 moderate,52 severe. Emotions; 24 mild, 35 moderate, 39 severe. Functioning: 21 mild, 32 moderate, 37 severe. Overal Score: 25 mild, 32 moderate, 44 severe. | Baseline and Day 85 | 
| Chronic Urticaria Quality of Life Questionnaire (Cu-Q2OL) by Treatment | The Cu-Q2OL is a 23-item CIU-specific health-related quality of life questionnaire. Patients rated their CIU symptoms and the impact of their CIU on various aspects of their lives. An overall score was calculated as well for the following domains: pruritus, swelling, impact on life activities, sleep problems, limits, and looks. Zero is the minmum score and 100 the maximum score. The higher score correlates to more disease activity. | Baseline and Day 85 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic idiopathic urticaria, CIU, Xolair, IGE025, FcεRI, IgE