Protocol Number: 09-I-0129

Title:

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

Number:

09-I-0129

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 60 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 per year, at least once within the last 2 months, and one episode per quarter 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 12 months.

- Participants will remain on the assigned regimen for 6 months or until they have experienced two anaphylactic events within 4 months that may be possibly related to the study drug, whichever comes first. At that time, the participant will be discontinued from drug administration.

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. 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 corticosteroids or other immunosuppressant medications

11. Pregnant or nursing women

12. Positive pregnancy urine test

13. 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):

Anaphylaxis

Allergic Reaction

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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