Protocol Number: 09-I-0129

Title:

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

Number:

09-I-0129

Summary:

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® (Registered Trademark)) 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 12 months. Patients will remain on the assigned regimen until they have experienced 2 anaphylactic events (post 24-hr window) determined to be unrelated to study drug or have been followed for 6 months, whichever comes first. After this point, the patient will be discontinued from drug administration until unblinding. This design ensures that no patient will have more than 2 anaphylactic episodes while on placebo. 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.

Sponsoring Institute:

National Institute of Allergy and Infectious Diseases (NIAID)

Recruitment Detail

Type: Participants currently recruited/enrolled

Gender: Male & Female

Referral Letter Required: Yes

Population Exclusion(s): Children

Eligibility Criteria:

INCLUSION CRITERIA:

Subject must be at least 18 years of age and no older than 60 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.

Documented anaphylaxis (mild-severe) at least 6 times per year, at least 1 within the last 2 months, and 1 episode per quarter with 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:

a. Respiratory compromise or gastrointestinal involvement (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced peak expiratory flow, hypoxemia, nausea, vomiting, or abdominal pain [Grade 2]*).

b. 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:

a. Respiratory compromise or gastrointestinal involvement (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced peak expiratory flow, hypoxemia, nausea, vomiting, or abdominal pain [Grade 2]*).

b. 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 drug (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. Known cause for anaphylaxis or flushing

3. Diagnosis of mastocytosis

4. Inability to provide informed consent

5. Inability or refusal to undergo a bone marrow biopsy and aspirate

6. HIV positive or other known immunodeficiency

7. Active or chronic hepatitis

8. Use of any other investigational agent within 30 days of the study

9. Current use of corticosteroids or other immunosuppressant medications

10. Pregnant or nursing women

11. Positive pregnancy urine test

12. IgE levels and subject's weight that cause dosing to be above standard dosing guidelines in the current Package Insert.

Special Instructions:

Currently Not Provided

Keywords:

Omalizumab

Idiopathic Anaphylaxis

Serum Tryptase

Placebo-Controlled

Adult

Recruitment Keyword(s):

None

Condition(s):

Anaphylaxis

Hypotension

Bronchospasm

Angioedema

Investigational Drug(s):

Omalizumab (Xolair)

Investigational Device(s):

None

Intervention(s):

Drug: Epinephrine

Procedure/Surgery: Bone Marrow Apsiration

Drug: Omalizumab (Xolair)

Supporting Site:

National Institute of Allergy and Infectious Diseases

Contact(s):

Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citation(s):

Thong BY, Cheng YK, Leong KP, Tang CY, Chng HH. Anaphylaxis in adults referred to a clinical immunology/allergy centre in Singapore.Singapore Med J. 2005 Oct;46(10):529-34.

Webb LM, Lieberman P. Anaphylaxis: a review of 601 cases. Ann Allergy Asthma Immunol. 2006 Jul;97(1):39-43.

Neugut AI, Ghatak AT, Miller RL. Anaphylaxis in the United States: an investigation into its epidemiology. Arch Intern Med. 2001 Jan 8;161(1):15-21.

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