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
Intervention: Epinephrine; Omalizumab (Xolair); Placebos
Intervention MeSH terms: Omalizumab; Epinephrine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 16.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No
Keywords: Omalizumab; Idiopathic Anaphylaxis; Serum Tryptase; Placebo-Controlled; Adult; Anaphylaxis; Allergic Reaction

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.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

        Volunteers must satisfy all of the following inclusion criteria to be eligible for this
        study.

        Subject must be at least 18 years of age and no older than 70 years of age.

        Diagnosis of idiopathic anaphylaxis, a diagnosis of exclusion, assigned after other causes
        of anaphylaxis and other diseases in the differential diagnoses have been considered.

        Anaphylaxis episodes (mild-severe) at least 6 times within the past 1 year period,
        documented according to medical records physician report, or patient report and 1 episode
        within the last 4 months, and with at least 1 of the following:

          1. Elevated serum tryptase above baseline within 2 hours of the event.

          2. Emergency room visit with documented anaphylaxis without an etiology established by
             the acute onset of an illness (minutes to several hours) with involvement of the skin,
             mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, swollen
             lips-tongue-uvula) [Grade 1]* and at least 1 of the following:

               1. Respiratory compromise or gastrointestinal involvement (e.g., dyspnea,
                  wheeze-bronchospasm, stridor, reduced peak expiratory flow, hypoxemia, nausea,
                  vomiting, or abdominal pain [Grade 2]*).

               2. Reduced blood pressure or associated symptoms of end-organ dysfunction (e.g.,
                  hypotonia [collapse], syncope, or incontinence [Grade 3]*).

          3. Hospitalization for anaphylaxis: hospital records with documented anaphylaxis without
             known cause established by the acute onset of an illness (minutes to several hours)
             with involvement of the skin, mucosal tissue, or both (e.g., generalized hives,
             pruritus or flushing, swollen lips-tongue-uvula) [Grade 1]*) and at least one of the
             following:

               1. Respiratory compromise or gastrointestinal involvement (e.g., dyspnea,
                  wheeze-bronchospasm, stridor, reduced peak expiratory flow, hypoxemia, nausea,
                  vomiting, or abdominal pain [Grade 2]*).

               2. Reduced blood pressure or associated symptoms of end-organ dysfunction (e.g.,
                  hypotonia [collapse], syncope, or incontinence [Grade 3]*).

          4. Letter of referral, with copies of pertinent medical history and laboratory tests,
             from prospective study participant s local physician.

          5. Ability to give informed consent.

          6. Women of childbearing potential must have a negative beta-HCG serum or urine pregnancy
             test prior to each injection, and must agree to practice abstinence or effective
             contraception from initiation of the protocol and for 3 months following the last
             infusion of the study agent (effective contraception methods include abstinence;
             surgical sterilization of either partner, barrier methods such as diaphragm, condom,
             cap, or sponge; or hormonal contraception).

               -  Severity grading of anaphylaxis

        EXCLUSION CRITERIA:

        A volunteer who satisfies any of the following exclusion criteria will be ineligible to
        participate in this study.

          1. Presence of conditions which, in the judgment of the investigator or the referring
             physician, may put the subject at undue risk for study participation or travel (such
             as an acute infection, severe thrombocytopenia, coronary artery disease, uncontrolled
             hypertension, congestive heart failure, chronic beta blocker therapy such as atenolol
             or metoprolol, or myeloproliferative disease).

          2. History of malignancy

          3. Known cause for anaphylaxis or flushing

          4. Diagnosis of mastocytosis

          5. Inability to provide informed consent

          6. Inability or refusal to undergo a bone marrow biopsy and aspirate

          7. HIV positive or other known immunodeficiency

          8. Active or chronic hepatitis

          9. Use of any other investigational agent within 30 days of the study

         10. Current use of chronic-oral corticosteroids or other immunosuppressant medications

         11. Pregnant or nursing women

         12. Positive pregnancy test

         13. IgE levels and subject s weight that cause dosing to be above dosing guidelines.