Prospective Double-blind Placebo-controlled Study of the Effect of Xolair (Omalizumab) in Chronic Urticaria Patients
Condition: Chronic Urticaria; Chronic Idiopathic Urticaria; Chronic Spontaneous Urticaria
MeSH terms: Urticaria; Chronic Urticaria
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      The aim of this study is to investigate the pathophysiological mechanism of omalizumab in
      patients with documented chronic urticaria who have complaints under standard antihistamine
      treatment. With this study the investigators will assess the correlation between Fc-IgE
      receptor downregulation as well as functionality and clinical response to omalizumab
      treatment in patients with chronic urticaria. This may be an approach for other diseases as
      well, where Fc-IgE receptor crosslinking are essential. The treatment time is set for a total
      of 4 monthly applications of omalizumab. According to the dosage recommendations of recent
      studies, fixed doses of 300 mg omalizumab are administered subcutaneously.
    

Detailed description: 
      Background

      Chronic urticaria (CU) is a frequent disease with a lifetime incidence of up to 25-30% of the
      population. Currently, CU treatment relies mainly on second generation antihistamines and is
      purely symptomatic. The disease tends to have a cyclical nature with spontaneous
      disappearance and frequent relapses. Some patients show a sufficient response to standard
      second generation antihistamines like (levo)cetirizine 10mg, (des)loratadine 5mg or
      terfenadine 120-180mg. Others need higher doses (up to 4-fold usual daily dose), often
      accompanied by sedation. Treatment may last for months, even years. If this first-line
      therapy is insufficient, the next step (sometimes even before use of excessively high doses
      of antihistamines) is to add first generation, even more sedating antihistamines, some of
      which have additional modes of action (e.g. anticholinergic effects in doxepin treatment). A
      considerable number of patients with CU need treatment escalations with leukotriene receptor
      blocking agents (e.g. montelukast), systemic corticosteroids (5-20mg prednisolon/d) or even
      cyclosporine (daily dose 3-5 mg/kg) or other immunosuppressive drugs used off-label. Such
      patients are often investigated more in detail to find an infection or autoimmune disease -
      often still without clear results.

      Different clinical findings suggest that the mast cell system in many patients with CU is
      "overactive" with increased releasability. Minor stress like scratching can already induce
      degranulation resulting in wheal-and-flare skin reactions. Therefore, a therapy directly
      aiming at a decrease in this mast cell "hyperreleasability" would be optimal. Omalizumab
      binds selectively to free IgE in plasma, inhibits its binding to Fc-IgE receptor on the
      surface of mast cells and basophils and reduces the number of Fc-IgE receptors on basophils
      in atopic patients. Significant reduction of Fc-IgE receptor density on the surface of
      circulating basophils has been found as early as 1 week after administration of omalizumab.
      In contrast to this, the onset of clinical efficacy of omalizumab in asthma is considered to
      take place relatively late, namely about 4 months after start of treatment. The
      pathophysiologic concepts of omalizumab treatment in allergic asthma are focused on the
      neutralisation of IgE, and less on the Fc-IgE receptor density. In allergology, free IgE in
      plasma is only relevant regarding Fc-IgE receptor density on effector cells. Therefore,
      Fc-IgE receptor density measurement might be an important parameter for mast cell and
      basophil "releasability" and therefore a good in vitro surrogate marker for their reactivity.
      E.g. it is well known that only about 50% of IgE-sensitized individuals show clinically
      relevant allergic symptoms. This difference between sensitization and allergy may also be due
      to Fc-IgE receptor density on mast cells and basophils. Flowcytometric determination of
      Fc-IgE receptor density on the surface of basophils and additional testing for the functional
      consequences of a change in this density (ability to crosslink Fc-IgE receptors by
      autoantibodies and allergens) raise the possibility to evaluate this hypothesis - using
      omalizumab as a drug being able to decrease Fc-IgE receptor density:

        1. Study data show that a fixed dose of 300 mg omalizumab is useful for the treatment of
           CU. The investigators assume that this effect is due to the decrease of Fc-IgE receptor
           density. Thus, the basophil Fc-IgE receptor density should be monitored quantitatively
           and functionally (see below) and correlated to clinical response.

        2. 30-40% of patients with CU have autoantibodies against Fc-IgE receptor or IgE itself,
           which can be measured in vitro (already via ELISA, flowcytometric via CD63 and CD203c
           upregulation on basophils). Decrease of Fc-IgE receptor density may decrease basophil
           reactivity and explain or be correlated to the clinical response in CU patients. At
           least three patients will be followed for reactivity to autoantibodies over the study
           period.

        3. Some patients with CU may also have an accompanying IgE-mediated allergy, which is most
           probably irrelevant for the CU, but offers the possibility of a functional test of
           basophil responsiveness to low concentrations of allergens - before (with presumably
           high Fc-IgE receptor density) and after omalizumab treatment (low Fc-IgE rec. density).
           At least three patients will be followed for allergen reactivity of basophils.

      Objective

      Primary objectives

      - Measurement of the kinetic of Fc-IgE receptor density change on basophils from patients
      with chronic urticaria with omalizumab compared to placebo

      Secondary objectives

        -  Change of responsiveness to Fc-IgE cross-linking dependent stimuli:

             -  incubation of patient's basophils with anti-IgE

             -  allergen induced cross-linking (only grass pollen and birch pollen allergic
                patients)

             -  comparison of serum on third party basophils

        -  Measurement of IL-3 hyperresponsiveness of basophils after Stimulation with anti-IgE and
           allergen

        -  Daily urticaria activity score

        -  Medication and rescue medication use

        -  German version of the Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL)

      Methods

      This is a monocentric, double-blind, randomized placebo-controlled trial, which aims to
      investigate the pathophysiological mechanism of omalizumab in patients with documented
      chronic urticaria who have complaints under standard antihistamine treatment.

      According to the inclusion criteria, 30 patients with diagnosed chronic urticaria will be
      recruited in our outpatient clinic. Omalizumab (Xolair®) is administered in fixed dose of 300
      mg in a total of 4 monthly doses according to the reference. A follow-up visit is planned 2
      months after the last injection.
    

Intervention name(s): Omalizumab (Xolair); Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Fixed dose of 300 mg omalizumab is subcutaneously administered in total 4 monthly doses; Fixed dose of placebo is subcutaneously administered in total 4 monthly doses
Intervention MeSH terms: Omalizumab
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Basic Science
Keywords: Omalizumab; Xolair; Urticaria; basophils; chronic Urticaria; Fc Receptor