A Randomized, Double-Blind, Placebo-Controlled Study of Omalizumab for Idiopathic Anaphylaxis
Condition: Anaphylaxis; Hypotension; Bronchospasm; Angioedema
MeSH terms: Bronchial Spasm; Hypotension; Angioedema; Anaphylaxis; Shock
Study type: Interventional
Phase: Phase 2

Summary: 
      Background:

        -  Omalizumab is an approved drug for the treatment of asthma by the Food and Drug
           Administration.

        -  Researchers are now studying this drug in a double-blind placebo-controlled manner to
           assess efficacy in patients with idiopathic anaphylaxis (recurrent hypersensitive
           allergic episodes for which a cause is not identified).

        -  The study will improve understanding of the mechanisms involved in anaphylactic
           reactions as a response to the downregulation (a decrease in the number of receptors on
           the surface of cells) in mast cell (a resident cell with several types of tissues)
           activation, and lead to the development of strategies to better prevent or treat
           anaphylaxis.

      Objectives:

        -  To determine whether treatment with omalizumab will reduce or prevent episodes of
           unprovoked anaphylaxis (an acute allergic reaction) in subjects with a history of
           idiopathic anaphylaxis.

        -  To assess pharmacodynamics (physiological effects of a drug) and identify patients with
           undiagnosed mastocytosis (rare disorders caused by too many mast cells).

        -  To investigate cellular and molecular mechanisms of signaling and the effect of
           omalizumab on mast cells or basophils (a cell in the leukocyte family that releases
           histamine, which affects allergic response) and explore other regulatory pathways that
           may be involved with modulation of mast cell degranulation.

      Eligibility:

        -  Patients between 18 and 70 years of age who have been diagnosed with idiopathic
           anaphylaxis, a diagnosis that is made only after other causes of anaphylaxis have been
           considered.

        -  Patients with documented anaphylaxis episodes (mild to severe) at least six times within
           the past 1 year period, at least once within the last 4 months, and with at least one of
           the following:

             -  Elevated serum tryptase above baseline within 2 hours of the event.

             -  Emergency room visit with documented anaphylaxis without a known cause established
                by the acute onset of an illness (minutes to several hours) with involvement of the
                skin, mucosal tissue, or both (generalized hives, itching or flushing, swollen
                lips-tongue-throat) and at least one of the following: (1) respiratory compromise
                or gastrointestinal involvement (shortness of breath, wheeze-bronchospasm, throat
                tightness, low oxygen levels, nausea, vomiting, or abdominal pain); or (2) reduced
                blood pressure or associated symptoms of end-organ dysfunction (collapse, loss of
                consciousness, or loss of bladder or bowel control).

             -  Hospitalization for anaphylaxis.

        -  Patients must provide a letter of referral, with copies of pertinent medical history and
           laboratory tests, from the prospective participant s local physician, and have the
           ability to give informed consent.

        -  Women with childbearing potential must have a negative pregnancy test, and must agree to
           practice abstinence or effective birth control from the start of the protocol and for 3
           months following the last injection of the study drug.

      Design:

        -  Participants will undergo a clinical evaluation, blood tests, and a bone marrow biopsy
           and aspirate.

        -  Participants will be randomized to either drug or placebo and will receive two doses of
           omalizumab or a matched placebo while hospitalized, followed by continued outpatient
           therapy, every 2 to 4 weeks, for up to 6 months.

        -  Participants will remain on the assigned regimen for 6 months or until they have
           experienced new onset of severe adverse event on one occasion within 24 hours of study
           medication that are related to the study drug, whichever comes first. At that time, the
           participant will be discontinued from drug administration.
    

Detailed description: 
      Anaphylaxis is a severe systemic reaction caused by release of mediators from mast cells and
      basophils. Manifestations include cutaneous, respiratory, cardiovascular, or gastrointestinal
      signs and symptoms. Although anaphylaxis is frequently attributed to exposure to specific
      foods, drugs, and insect venoms in sensitive individuals, a causative factor is not
      identified in 30% to 50% of patients with recurrent anaphylactic episodes (idiopathic
      anaphylaxis).

      Currently, therapeutic options for the treatment of idiopathic anaphylaxis are limited with
      variable efficacy. This pilot study will examine the hypothesis that omalizumab (Xolair )
      will decrease episodes of unexplained anaphylaxis in patients with idiopathic anaphylaxis.
      Omalizumab is approved for use in asthma. We will examine the safety profile and efficacy of
      omalizumab in patients with anaphylaxis. In addition, the study will investigate whether
      patients with anaphylaxis have unique molecular and cellular defects in mast cells that
      result in these cells being more susceptible to degranulation.

      The study will enroll patients with idiopathic anaphylaxis. Patients will undergo a clinical
      evaluation, blood tests, and a bone marrow biopsy and aspirate. Patients will be randomized
      to either drug or placebo and will receive, in a double-blind placebo-controlled approach, 2
      doses of omalizumab or a matched placebo while hospitalized, followed by continued outpatient
      therapy, every 2 to 4 weeks, for up to 6 months. Patients will remain on the assigned regimen
      if they have experienced anaphylactic events (post 24-hr window) determined to be unrelated
      to study drug or have been followed for 6 months, whichever comes first. These unrelated
      events would be determined by the PI not to jeopardize patient safety or restrict the use of
      additional therapy such as corticosteroids to control symptoms. After this point, the patient
      may be discontinued from drug administration until unblinding. This design ensures that no
      patient will have anaphylactic episodes while on placebo if other therapy is medically
      indicated. Research studies will be conducted to elucidate other markers or pathways of mast
      cell regulation.

      The primary outcome will be a reduction in the number and timing of anaphylactic events
      during the randomized phase. Secondary outcomes will include a reduction in surface IgE
      receptors on basophils, identification of mutations in c-kit, and evaluation of the efficacy
      of omalizumab on other mediator-induced symptoms associated with anaphylaxis. The study will
      improve the understanding of the mechanisms involved in anaphylactic reactions as a response
      to the downregulation of mechanisms involved in mast cell activation that could, in turn,
      lead to development of strategies to better prevent or treat anaphylaxis.
    

Intervention name(s): Epinephrine; Omalizumab (Xolair); Placebos
Intervention type(s): Drug; Drug; Drug
Intervention MeSH terms: Omalizumab; Epinephrine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: Omalizumab; Idiopathic Anaphylaxis; Serum Tryptase; Placebo-Controlled; Adult; Anaphylaxis; Allergic Reaction