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

Phase 2

Completed

Conditions: Angioedema
Hypotension
Bronchospasm
Anaphylaxis

Interventions: Drug: Epinephrine
Drug: Placebos
Drug: Omalizumab (Xolair)

Registration Number: NCT00890162

Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Brief 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 16

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Epinephrine	Subjects will receive two doses of placebo while hospitalized, followed by continued outpatient therapy, every 2 to 4 weeks, for up to 6 months.
Omalizumab	Epinephrine	Subjects will receive two doses of Omalizumab while hospitalized, followed by continued outpatient therapy, every 2 to 4 weeks, for up to 6 months.
Placebo	Placebos	Subjects will receive two doses of placebo while hospitalized, followed by continued outpatient therapy, every 2 to 4 weeks, for up to 6 months.
Omalizumab	Omalizumab (Xolair)	Subjects will receive two doses of Omalizumab while hospitalized, followed by continued outpatient therapy, every 2 to 4 weeks, for up to 6 months.

Primary Outcome Measures

Name	Time	Method
Reduction in the Number and Timing of Anaphylactic Events in Subjects With a History of Frequent Idiopathic Anaphylaxis.	6 months	To determine if treatment with omalizumab over 6 months will produce a reduction in the number and timing of anaphylactic events in subjects with a history of frequent idiopathic anaphylaxis. Ordinal outcome of participants based on number of events in 6 months after baseline and timing of first event. Events were calculated based on detailed event logs maintained by the patients and collected every 2-4 weeks based on injection schedule. Mean percent change in number of events experienced while on study agent for each subject and results presented as a group.

Secondary Outcome Measures