Efficacy Study of Omalizumab in Cholinergic Urticaria

Study Overview
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Brief Summary
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To demonstrate the efficacy and safety of Omalizumab in a new indication, that is cholinergic urticaria.

Detailed Description
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Physical urticarias, such as delayed pressure, cholinergic, dermatographism and cold urticaria, are highly disabling conditions[1]. Cholinergic urticaria occurs due to an active (e.g. exercise) or passive (e.g. hot bath) increase in core body temperature, causing itching and small hives with flare reaction on the trunk and limps that fade away upon cooling of the body[2]. As it is the case of chronic urticaria, physical urticarias have a great impact on patients' quality of life[3, 4]. However, these types of urticarias cause even more alteration on quality of life because of the limitations they cause in daily life activities, sports practicing[5] or work performance. In spite of the high morbidity of this disease and the impact on quality of life, there is no available treatment. Antihistamines that usually control other types of urticaria could only partially alleviate cholinergic urticaria. There is only one paper[6] that shows efficacy doubling the dose of cetirizine above the recommended dosage on the Summary of Product Characteristics (off-label dosage). The poor response to antihistamine is justified by the minimal role of histamine in its physiopathology and only after employing very high doses[7]. The etiology and pathogenesis of hive formation remains unknown, though it is recognized that mast cells are clearly involved[8]. On the other hand, it seems that desensitization or tolerance could be induced in cholinergic urticaria[9]. Thus as it is the case of drug desensitization, Immunoglobulin E (IgE) receptor must also play a role in the development of this physical urticaria[10]. In the past years, the monoclonal humanized anti-IgE antibody (Omalizumab) was shown to be effective in control cholinergic urticaria[11] not respondent to conventional therapies at maximum or off-label doses. A negative response was also reported for cholinergic urticaria[12]. Our rationale for this approach in this type of urticaria is that Omalizumab exerts an inhibitory action on mast cell activation, as is the case of desensitization. For that purpose, we will perform a multicenter, randomized, double-blind, placebo-controlled parallel clinical trial. We will include 24 patients including both female and male patients (age 14 years or older), non-respondent to antihistamines. Efficacy will be evaluated through the negativization of the European Academy of Allergy and Clinical Immunology (EAACI), European Dermatology Forum (EDF) and urticaria network e.V (UNEV) standardized exercise challenge test, Visual Analog Scale (VAS), Chronic Urticaria Quality of Life validated questionnaire[13], patients' card of symptoms and use of rescue medication. Additional measures of efficacy will also be: the number of dropouts in each treatment group; the leave days due of urticaria and Emergency Department visits. Finally, safety will be assessed by means of recording and evaluation of adverse reactions during treatment. As we previously stated, Omalizumab is not indicated for physical or other types of urticaria. The only indication is for treatment of moderate-to-severe allergic asthma. The hypothesis we are working on is that the monoclonal anti-IgE antibody Omalizumab could be as well effective in controlling physical urticaria symptoms in patients non-respondent to conventional therapy. We hypothesize that Omalizumab is able to revert the basophil or mast cell activation present in those urticaria types.

Official Title
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Multicenter Randomized, Double-blind, Placebo-controlled Parallel Clinical Trial to Assess Efficacy and Safety of Omalizumab (Xolair®) in a New Indication: Cholinergic Urticarial

Conditions
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Cholinergic Urticaria

Intervention / Treatment
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* Biological: Active
* Biological: Placebo
* Biological: Open labeled


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult female and male patients (age 14 years or older). Diagnosis of cholinergic urticaria trough clinical history and positive challenge test. Non-respondent to supra therapeutic doses of antihistamines (defined as 2x the maximal dose included in the drug labeling) Written informed consent. Exclusion Criteria: Pruritus related to dermatitis or other skin condition. Any systemic disease that hampers follow up or interpretation of data. Omalizumab treatment within the previous 12 months. Any exclusion criteria included in the drug labeling. Any other conditions that do not allow the accomplishment of the clinical trial requisites, such as the abuse of drugs or alcohol.

Ages Eligible for Study
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Minimum Age: 14 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active<br>Omalizumab 300 mg Subcutaneous route 300 mg dose (independent from total IgE, weight or high) | Biological: Active<br>* Two injections will be administered every four weeks for four months, we will administer 4 doses within 16 weeks<br>* Other names: Xolair;|
| Placebo Comparator: Placebo<br>Placebo Saline serum Subcutaneous route 0.6 ml saline serum with same volume as an active treatment | Biological: Placebo<br>* Two injections will be administered every four weeks for four months, we will administer 4 doses within 16 weeks<br>* Other names: Other Names: Saline serum;|
| Active Comparator: Open labeled<br>After the double blinded period, all patients from both arms will receive the active drug for 8 more months. | Biological: Open labeled<br>* Two injections will be administered every four weeks for 8 months, we will administer 4 doses within 32 weeks<br>* Other names: Xolair;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Negativization of the exercise challenge test | a. Our primary endpoint will be the negativization of the exercise challenge test: We will perform the exercise challenge test following the European Guidelines[14] for cholinergic urticaria. According with such guidelines, all centers will follow the same center standardized protocol. The patient will exercise in treadmill or running to the point of sweating and following for 15 more minutes, wearing warm clothing in a warm room. The test will be considered positive if exercise challenge leads to the typical rash over 10 minutes. | It will be assessed prior to the study, and subsequently each 4 weeks up to 12 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Chonic Urticaria Quality of life | Quality of Life: QoL will be evaluated through the Spanish validated version of Chronic Urticaria quality of life (CU-Q2oL) | It will be evaluated up to 48 weeks. | 
| Patients' card | Use of medication, VAS, daily symptoms, emergency visits, days off work. | It will be assessed up to 48 weeks. | 
| Treatment drop offs in each sequence |  | Up to 48 weeks. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cholinergic urticaria, Omalizumab