A Randomized, Double-Blind, Placebo-Controlled Study of Omalizumab for Idiopathic Anaphylaxis
A Randomized, Double-Blind, Placebo-Controlled Study of Omalizumab for Idiopathic Anaphylaxis
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.
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.
-  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.